Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy

ABSTRACT

The present invention relates to aminoindane derivatives of the formula (I) 
                         
or a physiologically tolerated salt thereof.
 
     The invention relates to pharmaceutical compositions comprising such aminoindane derivatives, and the use of such aminoindane derivatives for therapeutic purposes. The aminoindane derivatives are GlyT1 inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. patent application Ser. No. 13/207,030,filed on Aug. 10, 2011, which claims priority to U.S. Patent ApplicationNo. 61/373,590, filed on Aug. 13, 2010, the entire contents of all ofwhich are fully incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to aminoindane derivatives, pharmaceuticalcompositions comprising such aminoindane derivatives, and the use ofsuch aminoindane derivatives for therapeutic purposes. The aminoindanederivatives are GlyT1 inhibitors.

Dysfunction of glutamatergic pathways has been implicated in a number ofdisease states in the human central nervous system (CNS) including butnot limited to schizophrenia, cognitive deficits, dementia, Parkinsondisease, Alzheimer disease and bipolar disorder. A large number ofstudies in animal models lend support to the NMDA hypofunctionhypothesis of schizophrenia.

NMDA receptor function can be modulated by altering the availability ofthe co-agonist glycine. This approach has the critical advantage ofmaintaining activity-dependent activation of the NMDA receptor becausean increase in the synaptic concentration of glycine will not produce anactivation of NMDA receptors in the absence of glutamate. Since synapticglutamate levels are tightly maintained by high affinity transportmechanisms, an increased activation of the glycine site will onlyenhance the NMDA component of activated synapses.

Two specific glycine transporters, GlyT1 and GlyT2 have been identifiedand shown to belong to the Na/Cl-dependent family of neurotransmittertransporters which includes taurine, gamma-aminobutyric acid (GABA),proline, monoamines and orphan transporters. GlyT1 and GlyT2 have beenisolated from different species and shown to have only 50% identity atthe amino acid level. They also have a different pattern of expressionin mammalian central nervous system, with GlyT2 being expressed inspinal cord, brainstem and cerebellum and GlyT1 present in these regionsas well as forebrain areas such as cortex, hippocampus, septum andthalamus. At the cellular level, GlyT2 has been reported to be expressedby glycinergic nerve endings in rat spinal cord whereas GlyT1 appears tobe preferentially expressed by glial cells. These expression studieshave led to the suggestion that GlyT2 is predominantly responsible forglycine uptake at glycinergic synapses whereas GlyT1 is involved inmonitoring glycine concentration in the vicinity of NMDA receptorexpressing synapses. Recent functional studies in rat have shown thatblockade of GlyT1 with the potent inhibitor(N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])-sarcosine (NFPS)potentiates NMDA receptor activity and NMDA receptor-dependent long-termpotentiation in rat.

Molecular cloning has further revealed the existence of three variantsof GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which displays aunique distribution in the brain and peripheral tissues. The variantsarise by differential splicing and exon usage, and differ in theirN-terminal regions.

The physiological effects of GlyT1 in forebrain regions together withclinical reports showing the beneficial effects of GlyT1 inhibitorsarcosine in improving symptoms in schizophrenia patients suggest thatselective GlyT1 inhibitors represent a new class of antipsychotic drugs.

Glycine transporter inhibitors are already known in the art, forexample:

(see also Hashimoto K., Recent Patents on CNS Drug Discovery, 2006, 1,43-53; Harsing L. G. et al., Current Medicinal Chemistry, 2006, 13,1017-1044; Javitt D. C., Molecular Psychiatry (2004) 9, 984-997;Lindsley, C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6,771-785; Lindsley C. W. et al., Current Topics in Medicinal Chemistry,2006, 6, 1883-1896).

It was one object of the present invention to provide further glycinetransporter inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to aminoindane derivatives of the formula(I)

wherein

-   A is a 5- or 6-membered ring;-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    trialkylsilylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl,    alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl,    dialkylaminocarbonylaminoalkyl, alkylsulfonylaminoalkyl, (optionally    substituted arylalkyl)aminoalkyl, optionally substituted arylalkyl,    optionally substituted heterocyclylalkyl, cycloalkyl, alkylcarbonyl,    alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl,    aminocarbonyl, alkylaminocarbonyl, (halogenated alkyl)aminocarbonyl,    arylaminocarbonyl, alkenyl, alkynyl, optionally substituted aryl,    hydroxy, alkoxy, halogenated alkoxy, hydroxyalkoxy, alkoxyalkoxy,    aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,    alkylcarbonylaminoalkoxy, arylcarbonylaminoalkoxy,    alkoxycarbonylaminoalkoxy, arylalkoxy, alkylsulfonylaminoalkoxy,    (halogenated alkyl)sulfonylaminoalkoxy, arylsulfonylaminoalkoxy,    (arylalkyl)sulfonylaminoalkoxy, heterocyclylsulfonylaminoalkoxy,    heterocyclylalkoxy, aryloxy, heterocyclyloxy, alkylthio, halogenated    alkylthio, alkylamino, (halogenated alkyl)amino, dialkylamino,    di-(halogenated alkyl)amino, alkylcarbonylamino, (halogenated    alkyl)carbonylamino, arylcarbonylamino, alkylsulfonylamino,    (halogenated alkyl)sulfonylamino, arylsulfonylamino or optionally    substituted heterocyclyl;-   W is —NR⁸— or a bond;-   A¹ is optionally substituted alkylene or a bond;-   Q is —S(O)₂— or —C(O)—;-   Y is —NR⁹— or a bond;-   A² is optionally substituted alkylene, alkylene-CO—, —CO-alkylene,    alkylene-O-alkylene, alkylene-NR¹⁰-alkylene, optionally substituted    alkenylene, optionally substituted alkynylene, optionally    substituted arylene, optionally substituted heteroarylene or a bond;-   X¹ is —O—, —NR¹¹—, —S—, optionally substituted alkylene, optionally    substituted alkenylene, optionally substituted alkynylene;-   R² is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl,    —CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy,    halogenated alkoxy, alkoxycarbonyl, alkenyloxy, arylalkoxy,    alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl,    aminosulfonyl, amino, alkylamino, alkenylamino, nitro or optionally    substituted heterocyclyl, or two radicals R² together with the ring    atoms of A to which they are bound form a 5- or 6-membered ring;-   R³ is hydrogen, halogen, alkyl or alkoxy, or two radicals R³    together with the carbon atom to which they are attached form a    carbonyl group;-   R^(4a) is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, CH₂CN, arylC₄-alkyl,    cycloalkyl, —CHO, alkylcarbonyl, (halogenated alkyl)carbonyl,    arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,    alkenyl, —C(═NH)NH₂, —C(═NH)NHCN, alkylsulfonyl, arylsulfonyl,    amino, —NO or heterocyclyl;-   R^(4b) is hydrogen, alkyl, halogenated alkyl, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, CH₂CN, —CHO, alkylcarbonyl, (halogenated    alkyl)carbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,    alkylaminocarbonyl, alkenyl, —C(═NH)NH₂, —C(═NH)NHCN, alkylsulfonyl,    arylsulfonyl; amino, —NO or heterocyclyl; or-   R^(4a), R^(4b) together are optionally substituted alkylene, wherein    one —CH₂— of alkylene may be replaced by an oxygen atom or —NR¹⁶;-   X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond;-   X³ is —O—, —S—, >CR^(13a)R^(13b) or a bond;-   R⁵ is optionally substituted aryl, optionally substituted cycloalkyl    or optionally substituted heterocyclyl;-   R⁶ is hydrogen or alkyl;-   R⁷ is hydrogen or alkyl;-   R⁸ is hydrogen or alkyl;-   R⁹ is hydrogen, alkyl, cycloalkyl, aminoalkyl, optionally    substituted arylalkyl or heterocyclyl; or-   R⁹, R¹ together are alkylene; or-   R⁹ is alkylene that is bound to a carbon atom in A² and A² is    alkylene or to a carbon atom in X¹ and X¹ is alkylene;-   R¹⁰ is hydrogen, alkyl or alkylsulfonyl;-   R¹¹ is hydrogen or alkyl, or-   R⁹, R¹¹ together are alkylene,-   R^(12a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or    hydroxy;-   R^(12b) is hydrogen or alkyl, or-   R^(12a), R^(12b) together are carbonyl or optionally substituted    alkylene, wherein one —CH₂— of alkylene may be replaced by an oxygen    atom or —NR¹⁴—;-   R^(13a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclylalkyl, optionally substituted aryl or    hydroxy;-   R^(13b) is hydrogen or alkyl, or-   R^(13a), R^(13b) together are carbonyl or optionally substituted    alkylene, wherein one —CH₂— of alkylene may be replaced by an oxygen    atom or —NR¹⁵—;-   R¹⁴ is hydrogen or alkyl;-   R¹⁵ is hydrogen or alkyl; and-   R¹⁶ is hydrogen or alkyl,    or a physiologically tolerated salt thereof.

Thus, the present invention relates to aminoindane derivatives havingthe formula (Ia)

wherein A, R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a), R^(4b), X², X³, R⁵are as defined herein.

Thus, the term aminoindane derivative is used herein to denote inparticular aminoindanes and fused cyclopentanes wherein the benzene ringis replaced by a 5- or 6-membered heterocyclic ring.

Said compounds of formula (I), i.e., the aminoindane derivatives offormula (I) and their physiologically tolerated salts, are glycinetransporter inhibitors and thus useful as pharmaceuticals.

The present invention thus further relates to the compounds of formula(I) for use in therapy.

The present invention also relates to pharmaceutical compositions whichcomprise a carrier and a compound of formula (I).

In particular, said compounds, i.e., the aminoindane derivatives andtheir physiologically tolerated salts, are inhibitors of the glycinetransporter GlyT1.

The present invention thus further relates to the compounds of formula(I) for use in inhibiting the glycine transporter.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1 and corresponding methods of inhibiting theglycine transporter GlyT1.

Glycine transport inhibitors and in particular inhibitors of the glycinetransporter GlyT1 are known to be useful in treating a variety ofneurologic and psychiatric disorders.

The present invention thus further relates to the compounds of formula(I) for use in treating a neurologic or psychiatric disorder.

The present invention further relates to the compounds of formula (I)for use in treating pain.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for treating a neurologicor psychiatric disorder and corresponding methods of treating saiddisorders. The present invention also relates to the use of thecompounds of formula (I) in the manufacture of a medicament for treatingpain and corresponding methods of treating pain.

The present invention further relates to aminoindane derivatives offormula (II)

wherein L is an amino-protecting group, Y is NR⁹, and A², X¹, R², R³,R^(4a), R^(4b), X², X³, R⁵ and R⁹ are defined as above.

The aminoindane derivatives of formula (II) are useful as intermediatesin the preparation of GlyT1 inhibitors, in particular those of formula(I).

DETAILED DESCRIPTION OF THE INVENTION

Provided that the aminoindane derivatives of the formula (I) or (II) ofa given constitution may exist in different spatial arrangements, forexample if they possess one or more centers of asymmetry,polysubstituted rings or double bonds, or as different tautomers, it isalso possible to use enantiomeric mixtures, in particular racemates,diastereomeric mixtures and tautomeric mixtures, preferably, however,the respective essentially pure enantiomers, diastereomers and tautomersof the compounds of formula (I) or (II) and/or of their salts.

According to one embodiment, an enantiomer of the aminoindanederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵ are as defined herein.

According to another embodiment, an enantiomer of the aminoindanederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵ are as defined herein.

According to one embodiment, an enantiomer of the aminoindanederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵ are as defined herein.

According to another embodiment, an enantiomer of the aminoindanederivatives of the present invention has the following formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³, R⁵ are as defined herein.

The physiologically tolerated salts of the aminoindane derivatives ofthe formula (I) or (II) are especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, C₁-C₄-alkylsulfonic acids, such asmethanesulfonic acid, cycloaliphatic sulfonic acids, such asS-(+)-10-camphor sulfonic acid, aromatic sulfonic acids, such asbenzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylicacids and hydroxycarboxylic acids having 2 to 10 carbon atoms, such asoxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid,tartaric acid, citric acid, glycolic acid, adipic acid and benzoic acid.Other utilizable acids are described, e.g., in Fortschritte derArzneimittelforschung [Advances in drug research], Volume 10, pages 224ff., Birkhäuser Verlag, Basel and Stuttgart, 1966. The physiologicallytolerated salts of the aminoindane derivatives also include salts of aphysiologically tolerated anion with an aminoindane derivative whereinone or more than one nitrogen atom is quaternized, e.g. with an alkylresidue (e.g. methyl or ethyl).

The present invention moreover relates to compounds of formula (I) or(II) as defined herein, wherein at least one of the atoms has beenreplaced by its stable, nonradioactive isotope (e.g., hydrogen bydeuterium, ¹²C by ¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein atleast one hydrogen atom has been replaced by a deuterium atom.

Of course, such compounds contain more of the respective isotope thanthis naturally occurs and thus is anyway present in the compounds (I) or(II).

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one or more additional neutron than the normallyabundant isotope of the respective atom. Deuterated compounds have beenused in pharmaceutical research to investigate the in vivo metabolicfate of the compounds by evaluation of the mechanism of action andmetabolic pathway of the non-deuterated parent compound (Blake et al. J.Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are importantin the design of safe, effective therapeutic drugs, either because thein vivo active compound administered to the patient or because themetabolites produced from the parent compound prove to be toxic orcarcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.2-36, Academic Press, London, 1985; Kato et al., J. Labelled Comp.Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J.Physiol. Pharmacol., 77, 79-88 (1999).

Incorporation of a heavy atom particularly substitution of deuterium forhydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug. This effect is usually insignificant ifthe label is placed at a metabolically inert position of the molecule.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7:13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65:3; MacLennan A H et al.Am. J. Obstet Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. N.Y. Acad. Sci 1960 84: 736; Czakja D Metal., Am. J. Physiol.1961 201: 357). Higher deuterium concentrations, usually in excess of20%, can be toxic in animals. However, acute replacement of as high as15%-23% of the hydrogen in humans' fluids with deuterium was found notto cause toxicity (Blagojevic N et al. in “Dosimetry & TreatmentPlanning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling0 Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and USPatent Application Publication Nos. 20090137457; 20090131485;20090131363; 20090118238; 20090111840; 20090105338; 20090105307;20090105147; 20090093422; 20090088416; 20090082471, the methods arehereby incorporated by reference.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

Unless indicated otherwise, the term “substituted” means that a radicalis substituted with 1, 2 or 3, especially 1, substituent which are inparticular selected from the group consisting of halogen, C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, C₁-C₄-alkenyl, OH, SH, CN,CF₃, O—CF₃, COOH, O—CH₂—COOH, C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl, CONH₂, CONH—C₁-C₆-alkyl,SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂, SO₂N—(C₁-C₆-alkyl)₂, NH₂,NH—C₁-C₆-alkyl, N—(C₁-C₆-alkyl)₂, NH—(C₁-C₄-alkyl-C₆-C₁₂-aryl),NH—CO—C₁-C₆-alkyl, NH—SO₂—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, C₆-C₁₂-aryl,O—C₆-C₁₂-aryl, O—CH₂—C₆-C₁₂-aryl, CONH—C₆-C₁₂-aryl, SO₂NH—C₆-C₁₂-aryl,CONH—C₃-C₁₂-heterocyclyl, SO₂NH—C₃-C₁₂-heterocyclyl, SO₂—C₆-C₁₂-aryl,NH—SO₂—C₆-C₁₂-aryl, NH—CO—C₆-C₁₂-aryl, NH—SO₂—C₃-C₁₂-heterocyclyl,NH—CO—C₃-C₁₂-heterocyclyl and C₃-C₁₂-heterocyclyl, oxo (═O) being afurther substituent, wherein aryl and heterocyclyl in turn may beunsubstituted or substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

The term halogen denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine or chlorine.

C₁-C₄-Alkyl is a straight-chain or branched alkyl group having from 1 to4 carbon atoms. Examples of an alkyl group are methyl, C₂-C₄-alkyl suchas ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl ortert-butyl. C₁-C₂-Alkyl is methyl or ethyl, C₁-C₃-alkyl is additionallyn-propyl or isopropyl.

C₁-C₆-Alkyl is a straight-chain or branched alkyl group having from 1 to6 carbon atoms. Examples include methyl, C₂-C₄-alkyl as mentioned hereinand also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

Halogenated C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 orall of the hydrogen atoms are replaced by 1, 2, 3, 4 or a correspondingnumber of identical or different halogen atoms, such as inhalogenomethyl, dihalogenomethyl, trihalogenomethyl,(R)-1-halogenoethyl, (S)-1-halogenoethyl, 2-halogenoethyl,1,1-dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl,(R)-1-halogenopropyl, (S)-1-halogenopropyl, 2-halogenopropyl,3-halogenopropyl, 1,1-dihalogenopropyl, 2,2-dihalogenopropyl,3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl,(R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1-methylethyl,(R)-2,2-dihalogeno-1-methylethyl, (S)-2,2-dihalogeno-1-methylethyl,(R)-1,2-dihalogeno-1-methylethyl, (S)-1,2-dihalogeno-1-methylethyl,(R)-2,2,2-trihalogeno-1-methylethyl,(S)-2,2,2-trihalogeno-1-methylethyl, 2-halogeno-1-(halogenomethyl)ethyl,1-(dihalogenomethyl)-2,2-dihalogenoethyl, (R)-1-halogenobutyl,(S)-1-halogenobutyl, 2-halogenobutyl, 3-halogenobutyl, 4-halogenobutyl,1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl,4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, etc. Particular examplesinclude the fluorinated C₁-C₄-alkyl groups as defined, such astrifluoromethyl.

C₆-C₁₂-Aryl-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₆-C₁₂-aryl, such as in benzyl.

Hydroxy-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, wherein one or two hydrogen atoms are replaced by one ortwo hydroxyl groups, such as in hydroxymethyl, (R)-1-hydroxyethyl,(S)-1-hydroxyethyl, 2-hydroxyethyl, (R)-1-hydroxypropyl,(S)-1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,(R)-2-hydroxy-1-methylethyl, (S)-2-hydroxy-1-methylethyl,2-hydroxy-1-(hydroxymethyl)ethyl, (R)-1-hydroxybutyl,(S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.

C₁-C₆-Alkoxy-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms arereplaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4,in particular 1 or 2 carbon atoms, such as in methoxymethyl,(R)-1-methoxyethyl, (S)-1-methoxyethyl, 2-methoxyethyl,(R)-1-methoxypropyl, (S)-1-methoxypropyl, 2-methoxypropyl,3-methoxypropyl, (R)-2-methoxy-1-methylethyl,(S)-2-methoxy-1-methylethyl, 2-methoxy-1-(methoxymethyl)ethyl,(R)-1-methoxybutyl, (S)-1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl,4-methoxybutyl, ethoxymethyl, (R)-1-ethoxyethyl, (S)-1-ethoxyethyl,2-ethoxyethyl, (R)-1-ethoxypropyl, (S)-1-ethoxypropyl, 2-ethoxypropyl,3-ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methylethyl,2-ethoxy-1-(ethoxymethyl)ethyl, (R)-1-ethoxybutyl, (S)-1-ethoxybutyl,2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl.

Amino-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, in particular 1 or two carbon atoms, wherein onehydrogen atom is replaced by an amino group, such as in aminomethyl,2-aminoethyl.

C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a C₁-C₆-alkylamino group, inparticular by a C₁-C₄-alkylamino group, such as in methylaminomethyl,ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl,n-butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl ortert-butylaminomethyl.

Di-C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a di-C₁-C₆-Alkylamino group, inparticular by a di-C₁-C₄-alkylamino group, such as indimethylaminomethyl.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylcarbonylamino group, in particular by aC₁-C₄-alkylcarbonylamino group, such as in methylcarbonylaminomethyl,ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl,iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl,2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl ortertbutylcarbonylaminomethyl.

C₁-C₆-Alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylaminocarbonylamino group, in particular by aC₁-C₄-alkylaminocarbonylamino group, such as inmethylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl,n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl,nbutylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl,isobutylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

Di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by adi-C₁-C₆-alkylaminocarbonylamino group, in particular by adi-C₁-C₄-alkylaminocarbonylamino group, such as indimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl,dimethylaminocarbonylamino-propyl.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylsulfonylamino group, in particular by aC₁-C₄-alkylsulfonylamino group, such as in methylsulfonylaminomethyl,ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl,isopropylsulfonylaminomethyl, n-butylsulfonylaminomethyl,2-butylsulfonylaminomethyl, isobutylsulfonylaminomethyl ortert-butylsulfonylaminomethyl.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)amino group, in particular a(C₆-C₁₂-aryl-C₁-C₂-alkyl)amino group, such as in benzylaminomethyl.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₃-C₁₂-heterocyclyl, such as inN-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl.

C₃-C₁₂-Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbonatoms. In particular, 3 to 6 carbon atoms form the cyclic structure,such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclicstructure may be unsubstituted or may carry 1, 2, 3 or 4 C₁-C₄-alkylradicals, preferably one or more methyl radicals.

Carbonyl is >C═O.

C₁-C₆-Alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4, in particular1 or 2 carbon atoms as defined herein. Examples include acetyl,propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.

Halogenated C₁-C₆-alkylcarbonyl is C₁-C₆-alkylcarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms. Examples include fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

C₆-C₁₂-Arylcarbonyl is a radical of the formula R—C(O)—, wherein R is anaryl radical having from 6 to 12 carbon atoms as defined herein.Examples include benzoyl.

C₁-C₆-Alkoxycarbonyl is a radical of the formula R—O—C(O)—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethoxycarbonyl and tert-butyloxycarbonyl.

Halogenated C₁-C₆-alkoxycarbonyl is a C₁-C₆-alkoxycarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Aryloxycarbonyl is a radical of the formula R—O—C(O)—, wherein Ris an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenoxycarbonyl.

Cyano is —C≡N.

Aminocarbonyl is NH₂C(O)—.

C₁-C₆-Alkylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethylaminocarbonyl.

(Halogenated C₁-C₄-alkyl)aminocarbonyl is a C₁-C₄-alkylaminocarbonyl asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different hydrogen atoms.

C₆-C₁₂-Arylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylaminocarbonyl.

C₂-C₆-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl),1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and thelike. C₃-C₅-Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl,2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl,4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.

C₂-C₆-Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1-yl,2-propyn-2-yl and the like. C₃-C₅-Alkynyl is, in particular,2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl,4-pentyn-1-yl.

C₁-C₄-Alkylene is straight-chain or branched alkylene group having from1 to 4 carbon atoms. Examples include methylene and ethylene. A furtherexample is propylene.

C₂-C₄-Alkenylene is straight-chain or branched alkenylene group havingfrom 2 to 4 carbon atoms.

C₂-C₄-Alkynylene is straight-chain or branched alkynylene group havingfrom 2 to 4 carbon atoms. Examples include propynylene.

C₆-C₁₂-Aryl is a 6- to 12-membered, in particular 6- to 10-membered,aromatic cyclic radical. Examples include phenyl and naphthyl.

C₃-C₁₂-Arylene is an aryl diradical. Examples include phen-1,4-ylene andphen-1,3-ylene.

Hydroxy is —OH.

C₁-C₆-Alkoxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkyl group having from 1 to 6, in particular1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, 2-butoxy, iso-butoxy (2-methylpropoxy),tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy,3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy,1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy,2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy,2-ethylbutyloxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy,1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.

Halogenated C₁-C₆-alkoxy is a straight-chain or branched alkoxy grouphaving from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbonatoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms, such as in halogenomethoxy,dihalogenomethoxy, trihalogenomethoxy, (R)-1-halogenoethoxy,(S)-1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy,2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1-halogenopropoxy,(S)-1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy,1,1-dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy,3,3,3-trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy,(S)-2-halogeno-1-methylethoxy, (R)-2,2-dihalogeno-1-methylethoxy,(S)-2,2-dihalogeno-1-methylethoxy, (R)-1,2-dihalogeno-1-methylethoxy,(S)-1,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1-methylethoxy,(S)-2,2,2-trihalogeno-1-methylethoxy,2-halogeno-1-(halogenomethyl)ethoxy,1-(dihalogenomethyl)-2,2-dihalogenoethoxy, (R)-1-halogenobutoxy,(S)-1-halogenobutoxy, 2-halogenobutoxy, 3-halogenobutoxy,4-halogenobutoxy, 1,1-dihalogenobutoxy, 2,2-dihalogenobutoxy,3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy,etc. Particular examples include the fluorinated C₁-C₄ alkoxy groups asdefined, such as trifluoromethoxy.

C₁-C₆-Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein, wherein one or two hydrogenatoms are replaced by hydroxy. Examples include 2-hydroxyethoxy,3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2-hydroxyethoxy and thelike.

C₁-C₆-Alkoxy-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms as defined herein, wherein one ortwo hydrogen atoms are replaced by one or two alkoxy radicals havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy,3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy,ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy,2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.

Amino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4, preferably 1or 2 carbon atoms as defined herein, wherein one hydrogen atom isreplaced by an amino group. Examples include 2-aminoethoxy.

C₁-C₆-Alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by an alkylamino group having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein. Examples includemethylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy,isopropylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy,isobutylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy,2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy,2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy,2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy,2-(tert-butylamino)ethoxy.

Di-C₁-C₆-alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a dialkylamino group having from 1 to 6,preferably from 1 to 4 carbon atoms as defined herein. Examples includedimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino)ethoxy,2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy,2-(N-methyl-N-ethylamino)ethoxy.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylcarbonylamino group wherein thealkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylcarbonylaminomethoxy,ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy,isopropylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy,2-butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy,tert-butylcarbonylaminomethoxy, 2-(methylcarbonylamino)ethoxy,2-(ethylcarbonylamino)ethoxy, 2-(n-propylcarbonylamino)ethoxy,2-(iso-propylcarbonylamino)ethoxy, 2-(n-butylcarbonylamino)ethoxy,2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonylamino)ethoxy,2-(tert-butylcarbonylamino)ethoxy.

C₆-C₁₂-Arylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylcarbonylamino group as definedherein. Examples include 2-(benzoylamino)ethoxy.

C₁-C₆-Alkoxycarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkoxycarbonylamino group wherein thealkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methoxycarbonylaminomethoxy,ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy,isopropoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy,2-butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy,tertbutoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy,2-(ethoxycarbonylamino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy,2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy,2-(2-butoxycarbonylamino)ethoxy, 2-(iso-butoxycarbonylamino)ethoxy,2-(tert-butoxycarbonylamino)ethoxy.

C₂-C₆-Alkenyloxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinyloxy, allyloxy(2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy, methallyloxy(2-methylprop-2-en-1-yloxy) and the like. C₃-C₅-Alkenyloxy is, inparticular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy,3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy,4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

C₆-C₁₂-Aryl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by a C₆-C₁₂-aryl group as defined herein. Examplesinclude benzyloxy.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylsulfonylamino group having from 1to 6, preferably from 1 to 4 carbon atoms as defined herein. Examplesinclude 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy,2-[(2-methylpropyl)sulfonylamino]ethoxy.

(Halogenated C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by an alkylsulfonylamino grouphaving from 1 to 6, preferably from 1 to 4 carbon atoms as definedherein, wherein the alkyl group is halogenated. Examples include2-(trifluoromethylsulfonylamino)ethoxy.

C₆-C₁₂-Arylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylsulfonylamino group as definedherein. Examples include 2-(phenylsulfonylamino)ethoxy,2-(naphthylsulfonylamino)ethoxy.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino group, preferably by a(C₆-C₁₂-aryl-C₁-C₂-alkyl)sulfonylamino group. Examples include2-(benzylsulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by aC₃-C₁₂-heterocyclylsulfonylamino group as defined herein. Examplesinclude 2-(pyridin-3-yl-sulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₃-C₁₂-heterocyclyl group as definedherein. Examples include 2-(N-pyrrolidinyl)ethoxy,2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.

C₁-C₂-Alkylenedioxo is a radical of the formula —O—R—O—, wherein R is astraight-chain or branched alkylene group having from 1 or 2 carbonatoms as defined herein. Examples include methylenedioxo.

C₆-C₁₂-Aryloxy is a radical of the formula R—O—, wherein R is an arylgroup having from 6 to 12, in particular 6 carbon atoms as definedherein. Examples include phenoxy.

C₃-C₁₂-Heterocyclyloxy is a radical of the formula R—O—, wherein R is aC₃-C₁₂-heterocyclyl group having from 3 to 12, in particular from 3 to 7carbon atoms as defined herein. Examples include pyridin-2-yloxy.

C₁-C₆-Alkylthio is a radical of the formula R—S—, wherein R is an alkylradical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylthio, ethylthio, propylthio,butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio,3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl.

Halogenated C₁-C₆-alkylthio is a radical of the formula R—S—, wherein Ris a halogenated alkyl radical having from 1 to 6, preferably from 1 to4 carbon atoms as defined herein. Examples include halogenomethylthio,dihalogenomethylthio, trihalogenomethylthio, (R)-1-halogenoethylthio,(S)-1-halogenoethylthio, 2-halogenoethylthio, 1,1-dihalogenoethylthio,2,2-dihalogenoethylthio, 2,2,2-trihalogenoethylthio,(R)-1-halogenopropylthio, (S)-1-halogenopropylthio,2-halogenopropylthio, 3-halogenopropylthio, 1,1-dihalogenopropylthio,2,2-dihalogenopropylthio, 3,3-dihalogenopropylthio,3,3,3-trihalogenopropylthio, (R)-2-halogeno-1-methylethylthio,(S)-2-halogeno-1-methylethylthio, (R)-2,2-dihalogeno-1-methylethylthio,(S)-2,2-dihalogeno-1-methylethylthio,(R)-1,2-dihalogeno-1-methylethylthio,(S)-1,2-dihalogeno-1-methylethylthio,(R)-2,2,2-trihalogeno-1-methylethylthio,(S)-2,2,2-trihalogeno-1-methylethylthio,2-halogeno-1-(halogenomethyl)ethylthio,1-(dihalogenomethyl)-2,2-dihalogenoethylthio, (R)-1-halogenobutylthio,(S)-1-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio,4-halogenobutylthio, 1,1-dihalogenobutylthio, 2,2-dihalogenobutylthio,3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio,4,4,4-trihalogenobutylthio, etc. Particular examples include thefluorinated C₁-C₄-alkylthio groups as defined, such astrifluoromethylthio.

C₁-C₆-Alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl,2-methylbutylsulfinyl, 3-methylbutylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

C₁-C₆-Alkylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atomsas defined herein. Examples include methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

(Halogenated C₁-C₆-alkyl)sulfonyl is a C₁-C₆-alkylsulfonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Arylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylsulfonyl.

(C₆-C₁₂-Aryl-C₁-C₄-alkyl)sulfonyl is a radical of the formula R—S(O)₂—,wherein R is a C₆-C₁₂-aryl-C₁-C₄-alkyl radical, in particular aC₆-C₁₂-aryl-C₁-C₂-alkyl radical as defined herein. Examples includebenzylsulfonyl.

C₃-C₁₂-Heterocyclylsulfonyl is a radical of the formula R—S(O)₂—,wherein R is C₃-C₁₂-heterocyclyl as defined herein.

Aminosulfonyl is NH₂—S(O)₂—.

C₁-C₆-Alkylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbonatoms as defined herein. Examples include methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl,tert-butylaminosulfonyl.

Di-C₁-C₆-alkylaminosulfonyl is a radical of the formula RR′N—S(O)₂—wherein R and R′ are independently of each other an alkyl radical havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include dimethylaminosulfonyl, diethylaminosulfonyl,N-methyl-N-ethylaminosulfonyl.

C₆-C₁₂-Arylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an aryl radical having from 6 to 12, preferably 6 carbon atoms asdefined herein.

Amino is NH₂.

C₁-C₆-Alkylamino is a radical of the formula R—NH— wherein R is an alkylradical having from 1 to 6, in particular from 1 to 4 carbon atoms asdefined herein. Examples include methylamino, ethylamino, n-propylamino,iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino,tert-butylamino.

(Halogenated C₁-C₆-alkyl)amino is a C₁-C₆-alkylamino as defined herein,wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms arereplaced by 1, 2, 3, 4 or a corresponding number of identical ordifferent halogen atoms.

Di-C₁-C₆-alkylamino is a radical of the formula RR′N— wherein R and R′are independently of each other an alkyl radical having from 1 to 6, inparticular from 1 to 4 carbon atoms as defined herein. Examples includedimethylamino, diethylamino, N-methyl-N-ethylamino.

Di-(halogenated C₁-C₆-alkyl)amino is a di-C₁-C₆-alkylamino as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₁-C₆-Alkylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an alkyl radical having from 1 to 6, in particular from 1 to 4carbon atoms as defined herein.

Examples include acetamido (methylcarbonylamino), propionamido,n-butyramido, 2-methylpropionamido (isopropylcarbonylamino),2,2-dimethylpropionamido and the like.

(Halogenated C₁-C₆-alkyl)carbonylamino is a C₁-C₆-alkylcarbonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylcarbonylamino.

C₂-C₆-Alkenylamino is a radical of the formula R—NH—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinylamino, allylamino(2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino,methallylamino (2-methylprop-2-en-1-ylamino) and the like.C₃-C₅-Alkenylamino is, in particular, allylamino,1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino,methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino,4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or2-ethylprop-2-en-1-ylamino.

C₁-C₆-Alkylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an alkyl radical having from 1 to 6, in particular from 1to 4 carbon atoms as defined herein. Examples includemethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,isopropylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino,iso-butylsulfonylamino, tert-butylsulfonylamino.

(Halogenated C₁-C₆ alkyl)sulfonylamino is a C₁-C₆-alkylsulfonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an aryl radical having from 6 to 12 carbon atoms as definedherein. Examples include phenylsulfonylamino.

Nitro is —NO₂.

C₃-C₁₂-Heterocyclyl is a 3- to 12-membered heterocyclic radicalincluding a saturated heterocyclic radical, which generally has 3, 4, 5,6, or 7 ring forming atoms (ring members), an unsaturated non-aromaticheterocyclic radical, which generally has 5, 6 or 7 ring forming atoms,and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7ring forming atoms. The heterocyclic radicals may be bound via a carbonatom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclicradicals comprise 1 nitrogen atom as ring member atom and optionally 1,2 or 3 further heteroatoms as ring members, which are selected,independently of each other from O, S and N. Likewise preferredheterocyclic radicals comprise 1 heteroatom as ring member, which isselected from O, S and N, and optionally 1, 2 or 3 further nitrogenatoms as ring members.

Examples of C₃-C₁₂-heterocyclyl include:

C- or N-bound 3-4-membered, saturated rings, such as

2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thietanyl,1-azetidinyl, 2-azetidinyl, 3-azetidinyl;

C-bound, 5-membered, saturated rings, such as

tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl,tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl,1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl,tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl,1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl,tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl;C-bound, 6-membered, saturated rings, such astetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl,tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl,1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl,1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl,1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl,1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,tetrahydro-1,2-oxazin-6-yl;N-bound, 5-membered, saturated rings, such astetrahydropyrrol-1-yl (pyrrolidin-1-yl), tetrahydropyrazol-1-yl,tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl,tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;N-bound, 6-membered, saturated rings, such aspiperidin-1-yl, hexahydropyrimidin-1-yl, hexahydropyrazin-1-yl(piperazin-1-yl), hexahydropyridazin-1-yl, tetrahydro-1,3-oxazin-3-yl,tetrahydro-1,3-thiazin-3-yl, tetrahydro-1,4-thiazin-4-yl,tetrahydro-1,4-oxazin-4-yl (morpholin-1-yl), tetrahydro-1,2-oxazin-2-yl;C-bound, 5-membered, partially unsaturated rings, such as2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl,2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl,2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl,2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl,2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl,2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl,4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl,3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl,3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl,4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl,4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl,2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl,4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl,4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl,2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl,2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl,2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl,4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl,2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl,2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl,2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl,4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl,4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl,2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl,2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl,4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl,2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl,2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl,4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl,2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl,2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl,2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl,1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl,1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl;C-bound, 6-membered, partially unsaturated rings, such as2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl,1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl,2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl,4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl,1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl,1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl,2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl,2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl,1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl,1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl,1,2-dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl,3,4-dihydropyridin-3-yl, 3,4-dihydro-pyridin-4-yl,3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl,2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl,2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl,2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl,2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl,2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl,2H-5,6-dihydro-1,2-oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl,2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin-6-yl,2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl,2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl,4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro-1,2-oxazin-4-yl,4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl,4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl,4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl,2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl,2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl,2H-3,6-dihydro-1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl,2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl,2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1,2-oxazin-4-yl,2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl,2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl,2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1,2-thiazin-6-yl,2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl,2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl,3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl,1,2,3,6-tetrahydro-pyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl,4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl,4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl,4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl,4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl,3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl,3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl,1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl,1,2,3,4-tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl,1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl,2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl,2,3-dihydro-1,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl,2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl,2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl,2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl,4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl,4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl,4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl,6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl,6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl,2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl,2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl,2H-1,4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl,4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or3,4-dihydropyrimidin-6-yl;N-bound, 5-membered, partially unsaturated rings, such as2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl,2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl,2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl,2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl,2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl,2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;N-bound, 6-membered, partially unsaturated rings, such as1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl,2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl,2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl,2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl,2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl,1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl,3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl,1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl,2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl,4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl;C-bound, 5-membered, heteroaromatic rings, such as2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol-3-yl,pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl,imidazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl, tetrazol-5-yl;C-bound, 6-membered, heteroaromatic rings, such aspyridin-2-yl, pyridin-3-yl, pyridin-4-yl (4-pyridyl), pyridazin-3-yl,pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;N-bound, 5-membered, heteroaromatic rings, such aspyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, tetrazol-1-yl.

Heterocyclyl also includes bicyclic heterocycles, which comprise one ofthe described 5- or 6-membered heterocyclic rings and a furtheranellated, saturated or unsaturated or aromatic carbocycle, such as abenzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a furtheranellated 5- or 6-membered heterocyclic ring, this heterocyclic ringbeing saturated or unsaturated or aromatic. These include quinolinyl,isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl,benzothienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl andbenzimidazolyl. Examples of 5- or 6-membered heteroaromatic compoundscomprising an anellated cycloalkenyl ring include dihydroindolyl,dihydroindolizinyl, dihydroisoindolyl, dihydroquinolinyl,dihydroisoquinolinyl, chromenyl and chromanyl.

C₃-C₁₂-Heteroarylene is a heteroaryl diradical. Examples includepyrid-2,5-ylene and pyrid-2,4-ylene.

With respect to the compounds' capability of inhibiting glycinetransporter 1, the variables A, R, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴,X², X³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³R¹⁴, R¹⁵, R¹⁶, R¹⁷preferably have the following meanings which, when taken alone or incombination, represent particular embodiments of the aminoindanederivatives of the formula (I), (II) or any other formula disclosedherein.

In said formula (I) or (II), there may be one or more than onesubstituent R, R² and/or R³. More particularly, there may be up to 3substituents R², and up to 4 substituents R³. Preferably there is onesubstituent R and 1, 2 or 3 substituents R². Formula (I) may thus bedepicted as follows:

wherein a is 1, 2 or 3, b is 1, 2, 3, or 4 and c is 1. If there is morethan one radical R², these may be the same or different radicals. Ifthere is more than one radical R³, these may be the same or differentradicals.

A is a 5- or 6-membered ring which includes two carbon atoms from thecyclopentane, moiety to which A is fused. A may be a homocyclic orheterocyclic ring. The ring may be saturated, unsaturated non-aromaticor aromatic. According to a particular embodiment, A is a benzene ring,i.e. the compounds of formula (I) are aminoindanes of the formula:

As a heterocyclic ring, A may include 1, 2 or 3 heteroatoms as ringmember atoms, which are selected, independently of each other from N, Sand O. Preferred heterocyclic rings comprise 1 nitrogen atom as ringmember atom and optionally 1 or 2 further heteroatoms as ring members,which are selected, independently of each other from O, S and N.Likewise preferred heterocyclic rings comprise 1 heteroatom as ringmember atom, which is selected from O, S and N, and optionally 1 or 2further nitrogen atoms as ring member atoms. According to a particularembodiment, A is a heterocyclic ring selected from the group consistingof the following 5- or 6-membered heterocyclic rings:

In said formulae, hydrogen atoms are not depicted. This is meant toillustrate that the free valency of a carbon or nitrogen atom may beeither bound to a hydrogen atom, to R or to R². Accordingly, R and R²may be C- or N-bound at any position of ring A.

The skilled person will appreciate that some of the rings depicted abovemay be represented with a different structure, e.g. with hydrogen atomshaving other positions than those shown above, for instance as given inthe following structures:

Preferably, A is a heterocyclic ring selected from the group consistingof the following 5- or 6-membered heterocyclic rings:

According to a further particular embodiment, A is a heterocyclic ringselected from the group consisting of the following 5- or 6-memberedheterocyclic rings:

According to a preferred embodiment, A is a heterocyclic ring selectedfrom the group consisting of the following 5- or 6-membered heterocyclicrings:

If ring A is a 5-membered heterocyclic ring it is preferred that R isbound to G¹ or G², in particular G²:

In said formula, G¹, G² and G³ independently are —CH═, —CH₂—, —N═, —NH—,S or O, at least one of G¹, G² and G³ is —CH═ or —CH₂—, the dotted linerepresents a single or a double bond and R³, R⁴, X², X³, R⁵ are asdefined herein.

If ring A is 6-membered heterocyclic ring it is preferred that R isbound to G¹ or G², in particular G²:

In said formula, G¹, G², G³ and G⁴ independently are —CH═, —CH₂—, —N═,—NH—, S or O, at least one of G¹, G², G³ and G⁴ is —CH═ or —CH₂—, thedotted line represents a single or a double bond and R³, R⁴, X², X³, R⁵are as defined herein.

Heterocyclic compounds having the following partial structures arepreferred:

Heterocyclic compounds having the following partial structures areparticularly preferred:

In said formulae, R and R² are as defined herein. If there is more thanone radical R², these may be the same or different radicals.

R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl or n-pentyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g.trimethylsilylethyl), hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl(e.g. ethoxyethyl), amino C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl, C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-arylC₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g. cyclopropyl orcyclobutyl), C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, halogenatedC₁-C₆-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl, aminocarbonyl,C₁-C₆-alkylaminocarbonyl, (halogenated C₁-C₄-alkyl)aminocarbonyl,C₆-C₁₂-arylaminocarbonyl, C₂-C₆-alkenyl (e.g. prop-1,2-en-1-yl),C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl (e.g. phenyl,2-methylphenyl), hydroxy, C₁-C₆-alkoxy (e.g. tert-butyloxy), halogenatedC₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy,amino-C₁-C₄-alkoxy, C₁-C₆-alkylamino-C₁-C₄-alkoxy,di-C₁-C₆-alkylamino-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,(C₆-C₁₂-aryl-C₁-C₅-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino(e.g. dimethylamino), di-(halogenated C₁-C₆-alkyl)amino,C₁-C₆-alkylcarbonylamino, (halogenated C₁-C₆-alkyl)carbonylamino,C₆-C₁₂-arylcarbonylamino, C₁-C₆-alkylsulfonylamino, (halogenatedC₁-C₆-alkyl)sulfonylamino, C₆-C₁₂-arylsulfonylamino or optionallysubstituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 2-thienyl,4-methyl-2-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl,2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl,1-ethyl-1,2-diazol-4-yl, 1-difluoromethyl-1,2-diazol-4-yl,2-methyl-1,3-diazol-4-yl, 1-methyl-1,3-diazol-4-yl,2-methyl-1,3-thiazol-5-yl, 2,4-dimethyl-1,3-thiazol-5-yl,3-pyrrolidinyl, 1-methyl-pyrrol-3-yl, 2-pyridyl,1-methyl-1,2-diazol-3-yl, 1-methyl-3-trifluoromethyl-1,2-diazol-4-yl,1,2-dimethyl-1,3-diazol-4-yl, 5-methylisoxazol-3-yl or1-methyl-1,2,4-triazol-3-yl).

Preferably, R¹ is C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,sec-butyl, n-butyl or n-pentyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g.trimethylsilylethyl), C₁-C₆-alkoxyC₁-C₄-alkyl (e.g. ethoxyethyl),amino-C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl), C₂-C₆-alkenyl (e.g.prop-1,2-en-1-yl), optionally substituted C₆-C₁₂-aryl (e.g. phenyl),hydroxy, C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino,di-C₁-C₆-alkylamino or optionally substituted C₃-C₁₂-heterocyclyl (e.g.3-pyridyl, 2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl,5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl,1-methyl-1,2-diazol-4-yl, 1-ethyl-1,2-diazol-4-yl,1-difluoromethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl,1-methyl-1,3-diazol-4-yl, 2-methyl-1,3-thiazol-5-yl,2,4-dimethyl-1,3-thiazol-5-yl or 3-pyrrolidinyl).

In particular, R¹ is C₁-C₆-alkyl (e.g. n-propyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), or optionally substitutedC₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 1-methyl-1,2-diazol-4-yl,1-methyl-1,3-diazol-4-yl, 3-oxetanyl, 1-methylpyrrol-3-yl).

In connection with R¹, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl or naphthyl, substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄ haloalkyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, morpholino and piperidinyl. Thesame applies to substituted C₆-C₁₂-aryl in substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl.

In connection with R¹, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as pyridyl, thienyl, diazolyl,quinolinyl, piperidinyl, piperazinyl or morpholinyl, pyrrolyl,isoxazolyl and triazolyl being further examples of suchC₃-C₁₂-heterocyclyl, substituted with 1, 2 or 3 substituents selectedfrom the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₆-C₁₂-arylamino andC₃-C₁₂-heterocyclyl (e.g., morpholino or piperidinyl). The same appliesto substituted C₃-C₁₂-heteroaryl in substitutedC₃-C₁₂-heteroaryl-C₁-C₄-alkyl.

According to one embodiment, W is —NR⁸— and Y is a bond. According to analternative embodiment, W is a bond and Y is —NR⁹—. According to afurther alternative embodiment, W is a bond and Y is a bond, especiallyif R¹ is a nitrogen-bound radical, e.g. nitrogen-bound heterocyclyl suchas piperazinyl or morpholinyl.

According to one embodiment, Q is —S(O)₂—. According to an alternativeembodiment, Q is —C(O)—.

According to a particular embodiment, —W-A¹-Q-Y— is —W-A¹-S(O)₂—NR⁹—,—NR⁸—S(O)₂—, -A¹-S(O)₂— or —S(O)₂—. According to a further particularembodiment, —W-A¹-Q-Y— is —W-A¹-CO—NR⁹— or —NR⁸—CO—.

A¹ is optionally substituted C₁-C₄-alkylene or a bond. In connectionwith A¹, substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl and cyano. Preferably, A¹ is abond. If A¹ is C₁-C₄-alkylene, W is preferably —NR⁸—.

A² is optionally substituted C₁-C₄-alkylene (e.g. 1,2-ethylene or1,3-propylene), C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene,C₁-C₄-alkylene-O—C₁-C₄-alkylene, C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene,optionally substituted C₆-C₁₂-arylene, optionally substitutedC₆-C₁₂-heteroarylene or a bond. Additionally, A² may be optionallysubstituted C₂-C₄-alkenylene or optionally substituted C₂-C₄-alkynylene.Preferably, A² is optionally substituted C₁-C₄-alkylene (e.g.1,2-ethylene or 1,3-propylene). More preferably, A² is C₁-C₄-alkylene(e.g. 1,2-ethylene). Alternatively, it is preferred that A² isoptionally substituted C₆-C₁₂-arylene, in particular C₆-C₁₂-aryleneselected from the group consisting of phen-1,4-ylene and phen-1,3-ylene,or optionally substituted C₆-C₁₂-heteroarylene, in particularC₆-C₁₂-heteroarylene selected from the group consisting ofpyrid-2,5-ylene and pyrid-2,4-ylene. If A² is a bond, X¹ is preferablyoptionally substituted C₁-C₄-alkylene. Alternatively, if A² is a bond,X¹ is in particular optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

In connection with A², substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₂-C₄-alkenylene or substitutedC₂-C₄-alkynylene in particular includes C₂-C₄-alkenylene orC₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₆-C₁₂-arylene in particular includesC₆-C₁₂-arylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxycarbonyl,cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylsulfonyl, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, C₆-C₁₂-arylamino andC₃-C₁₂-heterocyclyl (e.g., morpholino or piperidinyl).

In connection with A², substituted C₆-C₁₂-heteroarylene in particularincludes C₆-C₁₂-heteroarylene substituted with 1, 2 or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g, morpholino orpiperidinyl).

X¹ is —O—, —NR¹¹—, —S— or optionally substituted C₁-C₄-alkylene (e.g.—CH₂—, 1,2-ethylene and 1,3-propylene). In connection with X¹,substituted C₁-C₄-alkylene in particular includes C₁-C₄-alkylenesubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.Additionally, X¹ may be optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene (e.g. propynylene). Inconnection with X¹, substituted C₂-C₄-alkenylene or substitutedC₂-C₄-alkynylene in particular includes C₂-C₄-alkenylene orC₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.Preferably, X¹ is —O—, —NR¹¹, —S—. More preferably, X¹ is —O—.Alternatively, it is preferred if X¹ is optionally substitutedC₁-C₄-alkylene (e.g. —CH₂— or 1,2-ethylene).

According to a particular embodiment, A² is a bond and X¹ is optionallysubstituted C₁-C₄-alkylene, optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

According to a particular embodiment, R¹—W-A¹-Q-Y-A²-X¹— isR¹—S(O)₂—NH-A²-X¹—, R¹—NH—S(O)₂-A²-X¹—, R¹—C(O)—NH-A²-X¹— orR¹—NH—C(O)-A²-X¹—.

According to a particular embodiment, the structural element —Y-A²-X¹—comprises at least 2, 3 or 4 atoms in the main chain. According tofurther particular embodiments the structural element —Y-A²-X¹— has upto 4, 5 or 6 atoms in the main chain, such as 2 to 6, 2 to 5 or 2 to 4atoms in the main chain, especially 2, 3 or 4 atoms in the main chain.

According to a further particular embodiment, —Y-A²-X¹— is—C₁-C₄-alkylene-O— or —NR⁹—C₁-C₄-alkylene-O—, with —Y-A²-X¹— preferablyhaving 2 to 6, 3 to 5 and especially 4 atoms in the main chain.Particular examples of —Y-A²-X¹— include —(CH₂)₃—O— and —NR⁹—(CH₂)₂—O—.In this particular embodiment, R⁹ is as defined herein and preferably R⁹is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl) or C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), or R⁹ is C₁-C₄-alkylene that is bound to a carbonatom in A² which is C₁-C₄-alkylene.

According to a further particular embodiment, —Y-A²-X¹— is—NR⁹—C₁-C₄-alkylene-(e.g. —NH—CH₂—, —NH—(CH₂)₂— or —NH—(CH₂)₃—), with—Y-A²-X¹— preferably having 2 to 6, 2 to 5, 2 to 4 and especially 2, 3or 4 atoms in the main chain. In this particular embodiment, R⁹ is asdefined herein and preferably R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methylor ethyl) or C₃-C₁₂-cycloalkyl (e.g. cyclopropyl); or R⁹ isC₁-C₄-alkylene that is bound to a carbon atom in X¹ which isC₁-C₄-alkylene.

According to a further particular embodiment, —Y-A²-X¹— is—NR⁹—C₂-C₄-alkenylene- or —NR⁹—C₂-C₄-alkynylene-(e.g. —NH—CH₂—C≡C—),with —Y-A²-X¹— preferably having 2 to 6, 3 to 5 and especially 4 atomsin the main chain. In this particular embodiment, R⁹ is as definedherein and preferably is R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl orethyl) or C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl). If A is aheterocyclic ring, this embodiment of —Y-A²-X¹— is particularlysuitable.

According to a further particular embodiment, —Y-A²-X¹— is—C₁-C₄-alkylene-(e.g. —(CH₂)₂—), with —Y-A²-X¹— preferably having 2 to6, 2 to 5, 2 to 4 and especially 2 atoms in the main chain. If A is aheterocyclic ring, this embodiment of —Y-A²-X¹— is particularlysuitable.

According to a further particular embodiment, the structural motif—Y-A²-X¹ as disclosed herein is bound to Q being —S(O)₂— or —C(O)—.Particular examples for this embodiment include heterocyclic compoundsof the invention wherein R is R¹—S(O)₂—Y-A²-X¹ or R¹—C(O)—Y-A²-X¹.

The radical R (i.e. the radical R¹—W-A¹-Q-Y-A²-X¹—) may, in principle,be bound to the 4-, 5-, 6- or 7-position of the aminoindane skeleton:

In said formulae, R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a), R^(4b), X²,X³, R⁵ are as defined herein.

Aminoindane derivatives having the radical R¹—W-A¹-Q-Y-A²-X¹— in the 5-,6-, 7-position are preferred.

Particularly preferred are aminoindane derivatives having the radicalR¹—W-A¹-Q-Y-A²-X¹— in the 6-position.

In addition to the radical R¹—W-A¹-Q-Y-A²-X¹—, the aminoindanederivatives of the invention may have one or more than one furthersubstituent bound to the ring A. In these positions, the skeleton of theaminoindane derivatives may thus be substituted with one or more thanone radical R². If there is more than one radical R², these may be thesame or different radicals. In particular, in 4-, 5-, 6- and/or7-position, the aminoindane skeleton may be substituted with one or morethan one radical R². The aminoindane derivatives of the invention maytherefore be represented by one of the following formulae:

wherein R^(2a), R^(2b), R^(2c), R^(2d) independently have one of themeanings given for R², and R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a),R^(4b), X², X³, R⁵ are as defined herein.

R² is hydrogen, halogen (e.g. fluorine), C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl,optionally substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms towhich they are bound form a 5- or 6 membered ring.

An optionally substituted 5- or 6-membered ring that is formed by tworadicals R² together with the ring atoms of A to which they are boundis, for instance, a benzene ring.

In connection with R², substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen and C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

In connection with R², substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as morpholinyl, pyrrolidinyl andpiperidinyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄ haloalkyl, cyano,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

Preferably, R² is hydrogen, halogen (e.g. fluorine) or C₁-C₆-alkoxy. Inparticular, R² is hydrogen or halogen (e.g. fluorine).

According to a particular embodiment, the aminoindane derivatives of theinvention have one of the following formulae:

wherein R¹, W, A¹, Q, Y, A², X¹, R², R³, R^(4a), R^(4b), X², X³, R⁵ areas defined herein.

In 1-, 2-, and/or 3-position, the aminoindane derivatives of theinvention may be substituted with one or more than one radical R³. Ifthere is more than one radical R³, these may be the same or differentradicals. The aminoindane derivatives of the invention may therefore berepresented by the following formula:

wherein R^(3a), R^(3b), R^(3c), R^(3d) independently have one of themeanings given for R³, and A, R, R², R³, R^(4a), R^(4b), X², X³, X⁵ areas defined herein.

According to a particular embodiment, the aminoindane derivatives of theinvention have one of the following formulae:

wherein R^(3a), R^(3b), R^(3d) independently have the meaning of R³ andA, R, R², R³, R^(4a), R^(4b), X², X³, R⁵ are as defined herein.

R³ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, or two radicals R³together with the carbon atom to which they are attached form a carbonylgroup.

Preferably, R³ is hydrogen or C₁-C₆-alkyl. In particular, R³ ishydrogen.

R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl orisopropyl), C₃-C₁₂-cycloalkylC₁-C₄-alkyl (e.g. cyclopropylmethyl),halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl),hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₆-C₁₂-aryl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g. cyclopropyl), CH₂CN,—CHO, C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl orisopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl,1,1,1-trifluoroeth-2-ylcarbonyl or 1,1,1-trifluoroprop-3-ylcarbonyl),C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl), C₁-C₄-alkoxycarbonyl (e.g.ethoxycarbonyl or tert-butyloxycarbonyl), C₆-C₁₂-aryloxycarbonyl (e.g.phenoxycarbonyl), C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂,—C(═NH)NHCN, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl (e.g. 3-oxetanyl).

Preferably, R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl,n-propyl or isopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl), halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or2,2,2-trifluoroethyl), amino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl (e.g. cyclopropyl), CH₂CN, C₁-C₄-alkylcarbonyl (e.g.methylcarbonyl or isopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl(e.g. fluoromethylcarbonyl, difluoromethylcarbonyl ortrifluoromethylcarbonyl), C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl),C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl),C₆-C₁₂-aryloxycarbonyl (e.g. phenoxycarbonyl), —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, amino, —NO or C₃-C₁₂-heterocyclyl (e.g.3-oxetanyl).

In particular, R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl),C₃-C₁₂-cycloalkyl (e.g. cyclopropyl), or C₃-C₁₂-heterocyclyl (e.g.3-oxetanyl), or C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl).

R^(4b) is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl), halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenatedC₁-C₄-alkyl)carbonyl, C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl,—C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl,amino, —NO or C₃-C₁₂-heterocyclyl.

Preferably, R^(4b) is hydrogen, C₁-C₆-alkyl (e.g. methyl). Inparticular, R^(4b) is hydrogen.

Alternatively, R^(4a), R^(4b) together are optionally substitutedC₁-C₆-alkylene (e.g. 1,4-butylene, 1,3-propylene, 2-fluoro-but-1,4-yleneor 1-oxo-but-1,4-ylene, a further example being 2-methyl-1,3-propylene,2,2-dimethyl-1,3-propylene, or 2-methyl-2-hydroxy-1,3-propylene),wherein one —CH₂— of C₁-C₆-alkylene may be replaced by an oxygen atom(e.g. —CH₂—CH₂—O—CH₂—CH₂—) or —NR¹⁶.

In connection with R^(4a) and R^(4b), substituted C₁-C₆-alkylene inparticular includes C₁-C₆-alkylene substituted with 1, 2 or 3substituents selected from the group consisting of halogen (e.g. fluoro,chloro), C₁-C₄-alkyl (e.g. methyl), cyano, hydroxy, and C₁-C₄-alkoxy.

X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond. Preferably, X² is>CR^(12a)R^(12b).

X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond. Preferably, X³ is abond.

Thus, it is preferred if X² is >CR^(12a)R^(12b) and X³ is a bond.

R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl,optionally substituted C₆-C₁₂-aryl or hydroxy. Preferably, R^(12a) ishydrogen or C₁-C₆-alkyl.

R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino C₁-C₄-alkyl, di-C₁-C₆-alkylamino C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. Preferably, R^(13a) is hydrogen or C₁-C₆-alkyl.

In connection with R^(12a) and R^(13a), substituted C₁-C₆-alkyl inparticular includes C₁-C₆-alkyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, hydroxy, C₁-C₄-alkoxy andamino.

In connection with R^(12a) and R^(13a), substituted C₆-C₁₂-aryl inparticular includes C₆-C₁₂-aryl, such as phenyl, substituted with 1, 2or 3 substituents selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

R^(12b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(12b) is hydrogen.

R^(13b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(13b) is hydrogen.

Alternatively, R^(12a) and R^(12b), or R^(13a) and R^(13b), together aretogether are carbonyl or, preferably, optionally substitutedC₁-C₄-alkylene (e.g. 1,3-propylene), wherein one —CH₂— of C₁-C₄-alkylenemay be replaced by an oxygen atom or —NR¹⁴—.

In connection with R^(12a) and R^(12b), or R^(13a) and R^(13b),substituted C₁-C₄-alkylene in particular includes C₁-C₄-alkylenesubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxyand C₁-C₄-haloalkoxy.

According to a particular embodiment, R^(12a) is C₁-C₆-alkyl and R^(12b)is hydrogen or C₁-C₆-alkyl, or R^(13a) is C₁-C₆-alkyl and R^(13b) ishydrogen or C₁-C₆-alkyl.

According to a further particular embodiment, R^(12a) is hydrogen andR^(12b) is hydrogen, or R^(13a) is hydrogen and R^(13b) is hydrogen.

According to a further particular embodiment, R^(12a) and R^(12b)together are optionally substituted 1,3-propylene, or R^(13a) andR^(13b) together are optionally substituted 1,3-propylene.

R⁵ is optionally substituted C₆-C₁₂-aryl (e.g. phenyl, 2-fluorophenyl,2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl; 3-cyanophenyl,3-methylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl,2,4-dichlorophenyl or 3,4-dichlorophenyl,), optionally substitutedC₃-C₁₂-cycloalkyl (e.g. cyclohexyl) or optionally substitutedC₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-cycloalkyl in particularincludes C₃-C₁₂-cycloalkyl, such as cyclopropyl or cyclohexyl,substituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, optionally substituted C₁-C₆-alkyl, halogenatedC₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, amino,C₁-C₆-alkylamino, di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen (e.g. F, Cl, Br),optionally substituted C₁-C₆-alkyl (e.g. methyl), halogenatedC₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy, C₁-C₆-alkoxy (e.g.methoxy), halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, optionally substitutedC₁-C₆-alkyl, halogenated C₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy,halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylaminoand C₃-C₁₂-heterocyclyl.

In connection with R⁵, C₃-C₁₂-heterocyclyl in particular isC₃-C₁₂-heteroaryl.

Preferably, R⁵ is optionally substituted C₆-C₁₂-aryl, in particular asin the aminoindane derivatives of the formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³ are as defined herein, andR^(17a), R^(17b), R^(17c), R^(17d), R^(17e) independently are hydrogen,halogen (e.g. F, Cl or Br), optionally substituted C₁-C₆-alkyl (e.g.methyl), halogenated C₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy,C₁-C₆-alkoxy (e.g. methoxy), amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino or C₃-C₁₂-heterocyclyl.

It is also preferred if R⁵ is optionally substituted C₆-C₁₂-heteroaryl,in particular as in the aminoindane derivatives of the formula:

wherein A, R, R², R³, R^(4a), R^(4b), X², X³ are as defined herein, andR^(17b), R^(17c), R^(17d), R^(17e) independently are hydrogen, halogen(e.g. F, Cl or Br), optionally substituted C₁-C₆-alkyl (e.g. methyl),halogenated C₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy,C₁-C₆-alkoxy (e.g. methoxy), amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino or C₃-C₁₂-heterocyclyl.

According to a particular embodiment, the invention relates toaminoindane derivatives of the formula:

wherein A, R, R², R³, R^(4a), R^(4b), R⁵ are as defined herein, R⁵preferably being optionally substituted aryl and in particularoptionally substituted phenyl as disclosed herein.

In connection with R⁵ or R^(17a), R^(17b), R^(17c), R^(17d), R^(17e),substituted C₁-C₆-alkyl in particular includes C₁-C₆-alkyl, especiallyC₁-C₄-alkyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of hydroxy, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl (e.g. morpholinyl orpiperidinyl).

According to a particular embodiment, R^(17a), R^(17b), R^(17d), R^(17e)are hydrogen and R^(17c) is different from hydrogen(para-mono-substitution).

According to a further particular embodiment, R^(17a), R^(17c), R^(17d),R^(17e) are hydrogen and R^(17b) is different from hydrogen(meta-mono-substitution).

In connection with R^(17a), R^(17b), R^(17c), R^(17d), R^(17e),C₃-C₁₂-heterocyclyl in particular includes morpholinyl, imidazolyl andpyrazolyl.

R⁶ is hydrogen or C₁-C₆-alkyl. Preferably, R⁶ is hydrogen.

R⁷ is hydrogen or C₁-C₆-alkyl. Preferably, R⁷ is hydrogen.

R⁸ is hydrogen or C₁-C₆-alkyl. Preferably, R⁸ is hydrogen.

R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl), C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), amino-C₁-C₆-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl or C₃-C₁₂-heterocyclyl (e.g. 3-azetidinyl).Preferably, R⁹ is hydrogen or C₁-C₆-alkyl (e.g. methyl or ethyl).

According to a particular embodiment, R⁹ and R¹ together areC₁-C₄-alkylene (e.g. 1,3-1,2-ethylene or propylene) so as that R⁹ and R¹together with the atom in Q to which R¹ is bound and the nitrogen atomto which R⁹ is bound form an heterocyclic ring having, in particular, 4,5 or 6 ring member atoms (including the nitrogen atom and Q). With W andA¹ both being a bond, such a ring may be represented by the followingpartial structure:

wherein Q is as defined herein (e.g. S(O)₂) and n is 0, 1, 2, 3 or 4.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in A² and A²is C₁-C₄-alkylene so that R⁹ and at least part of A² together with thenitrogen atom to which R⁹ is bound form an N-containing heterocyclicring having, in particular, 4, 5, 6 or 7 ring member atoms (includingthe nitrogen atom). Such a ring may be represented by the followingpartial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. In this particular embodiment, X¹ preferablyis —O—. Particular combinations of p, r and q include p=1, r=0, q=1; andp=1, r=0, q=0. Alternatively, p is 0, r is 3 and q is 1, with X¹preferably being —O—.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in X¹ and X¹is C₁-C₄-alkylene (e.g. 1,2-ethylene) so that R⁹ and at least part of X¹together with the nitrogen atom to which R⁹ is bound form anN-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ringmember atoms (including the nitrogen atom). With A² being a bond, such aring may be represented by the following partial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. Particular combinations of p, r and q includep=1, r=0, q=0.

R¹⁰ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl. Preferably, R¹⁰ ishydrogen.

R¹¹ is hydrogen or C₁-C₆-alkyl. Preferably, R¹¹ is hydrogen.

Alternatively, R⁹, R¹¹ together are C₁-C₄-alkylene (e.g. ethylene).

R¹⁴ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁴ is hydrogen.

R¹⁵ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁵ is hydrogen.

R¹⁶ is hydrogen or C₁-C₆-alkyl. Preferably, IV is hydrogen.

Particular embodiments of aminoindane derivatives of the inventionresult if

-   A is a benzene ring;-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is C₁-C₆-alkyl (e.g. n-propyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl    (e.g. cyclopropylmethyl), C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), or    optionally substituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl,    1-methyl-1,2-diazol-4-yl, 1-methyl-1,3-diazol-4-yl, 3-oxetanyl,    1-methylpyrrol-3-yl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂—;-   Y is —NR⁹— or a bond;-   A² is C₁-C₄-alkylene (e.g. 1,2-ethylene) or a bond;-   X¹ is —O— or optionally substituted C₁-C₄-alkylene (e.g. methylene,    1,2-ethylene);-   R² is hydrogen or halogen (e.g. fluorine);-   R³ is hydrogen;-   R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl), C₃-C₁₂-cycloalkyl    (e.g. cyclopropyl), C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl), or    optionally substituted C₃-C₁₂-heterocyclyl (e.g. 3-oxetanyl);-   R^(4b) is hydrogen; or-   R^(4a), R^(4b) together are optionally substituted C₁-C₆-alkylene    (e.g. 1,3-propylene, 1,4-butylene, 2-methyl-1,3-propylene,    2,2-dimethyl-1,3-propylene, or 2-methyl-2-hydroxy-1,3-propylene),    wherein one —CH₂— of C₁-C₆-alkylene may be replaced by an oxygen    atom (e.g. —CH₂—CH₂—O—CH₂—CH₂—);-   X² is >CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. phenyl, 2-fluorophenyl,    2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl,    3-trifluoromethylphenyl);-   R⁹ is hydrogen, or-   R⁹ is C₁-C₄-alkylene (e.g. methylene) that is bound to a carbon atom    in X¹ and X¹ is C₁-C₄-alkylene (e.g. 1,2-ethylene);-   R^(12a) is hydrogen;-   R^(12b) is hydrogen; or-   R^(12a), R^(12b) together are C₁-C₄-alkylene (e.g. 1,3-propylene).

Further particular embodiments of aminoindane derivatives of theinvention result if

-   A is a benzene ring;-   R is R¹—W-A¹-Q-Y-A²-X¹—;-   R¹ is C₁-C₆-alkyl (e.g. n-propyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl    (e.g. cyclopropylmethyl), C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), or    optionally substituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl,    1-methyl-1,2-diazol-4-yl, 1-methyl-1,3-diazol-4-yl, 3-oxetanyl,    1-methylpyrrol-3-yl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂—;-   Y is —NR⁹— or a bond;-   A² is C₁-C₄-alkylene (e.g. 1,2-ethylene) or a bond;-   X¹ is —O— or optionally substituted C₁-C₄-alkylene (e.g. methylene,    1,2-ethylene);-   R² is hydrogen or halogen (e.g. fluorine);-   R³ is hydrogen;-   R^(4a) is hydrogen, C₁-C₆-alkyl (e.g. methyl), C₃-C₁₂-cycloalkyl    (e.g. cyclopropyl) or optionally substituted C₃-C₁₂-heterocyclyl    (e.g. 3-oxetanyl);-   R^(4b) is hydrogen; or-   R^(4a), R^(4b) together are C₁-C₆-alkylene (e.g. 1,3-propylene,    1,4-butylene), wherein one —CH₂— of C₁-C₆-alkylene may be replaced    by an oxygen atom (e.g. —CH₂—CH₂—O—CH₂—CH₂—);-   X² is >CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. phenyl, 2-fluorophenyl,    2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl,    3-trifluoromethylphenyl);-   R⁹ is hydrogen, or-   R⁹ is C₁-C₄-alkylene (e.g. methylene) that is bound to a carbon atom    in X¹ and X¹ is C₁-C₄-alkylene (e.g. 1,2-ethylene);-   R^(12a) is hydrogen;-   R^(12b) is hydrogen; or-   R^(12a), R^(12b) together are C₁-C₄-alkylene (e.g. 1,3-propylene).

Further particular compounds of the present invention are the individualaminoindane derivatives of the formula (Id) as listed in the followingtables 1 to 24 and physiologically tolerated salts thereof:

Table 1

Compounds of the formula (Id) wherein R² is hydrogen, R¹⁷ is hydrogenand the combination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b)for a compound in each case corresponds to one line of Table A (A-1 toA-480).

Table 2

Compounds of the formula (Id) wherein R² is hydrogen, R¹⁷ is 3-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 3

Compounds of the formula (Id) wherein R² is hydrogen, R¹⁷ is 3-Cl andthe combination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 4

Compounds of the formula (Id) wherein R² is hydrogen, R¹⁷ is 3-CF₃ andthe combination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 5

Compounds of the formula (Id) wherein R² is hydrogen, R¹⁷ is 2-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 6

Compounds of the formula (Id) wherein R² is hydrogen, R¹⁷ is 2-Cl andthe combination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 7

Compounds of the formula (Id) wherein R² is 5-F, R¹⁷ is hydrogen and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 8

Compounds of the formula (Id) wherein R² is 5-F, R¹⁷ is 3-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 9

Compounds of the formula (Id) wherein R² is 5-F, R¹⁷ is 3-Cl and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 10

Compounds of the formula (Id) wherein R² is 5-F, R¹⁷ is 3-CF₃ and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 11

Compounds of the formula (Id) wherein R² is 5-F, R¹⁷ is 2-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds tone line of Table A (A-1 to A-480).

Table 12

Compounds of the formula (Id) wherein R² is 5-F, R¹⁷ is 2-Cl and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 13

Compounds of the formula (Id) wherein R² is 7-F, R¹⁷ is hydrogen and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 14

Compounds of the formula (Id) wherein R² is 7-F, R¹⁷ is 3-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 15

Compounds of the formula (Id) wherein R² is 7-F, R¹⁷ is 3-Cl and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 16

Compounds of the formula (Id) wherein R² is 7-F, R¹⁷ is 3-CF₃ and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 17

Compounds of the formula (Id) wherein R² is 7-F, R¹⁷ is 2-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 18

Compounds of the formula (Id) wherein R² is 7-F, R¹⁷ is 2-Cl and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 19

Compounds of the formula (Id) wherein R² is 4-F, R¹⁷ is hydrogen and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 20

Compounds of the formula (Id) wherein R² is 4-F, R¹⁷ is 3-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 21

Compounds of the formula (Id) wherein R² is 4-F, R¹⁷ is 3-Cl and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 22

Compounds of the formula (Id) wherein R² is 4-F, R¹⁷ is 3-CF₃ and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 23

Compounds of the formula (Id) wherein R² is 4-F, R¹⁷ is 2-F and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

Table 24

Compounds of the formula (Id) wherein R² is 4-F, R¹⁷ is 2-Cl and thecombination of R¹, —Y-A²-X¹—, >CR^(12a)R^(12b), R^(4a), R^(4b) for acompound in each case corresponds to one line of Table A (A-1 to A-480).

R¹ —Y—A²—X¹— >CR^(12a)R^(12b) R^(4a), R^(4b) A-1.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-2.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-3.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-4.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-5.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-6.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-7.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-8.

—NH—(CH₂)₂—O— —CH₂— —CH₃, H A-9.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-10.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-11.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-12.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-13.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-14.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-15.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-16.

—NH—(CH₂)₂ —CH₂— —CH₃, H A-17.

—NH—CH₂— —CH₂— —CH₃, H A-18.

—NH—CH₂— —CH₂— —CH₃, H A-19.

—NH—CH₂— —CH₂— —CH₃, H A-20.

—NH—CH₂— —CH₂— —CH₃, H A-21.

—NH—CH₂— —CH₂— —CH₃, H A-22.

—NH—CH₂— —CH₂— —CH₃, H A-23.

—NH—CH₂— —CH₂— —CH₃, H A-24.

—NH—CH₂— —CH₂— —CH₃, H A-25.

—CH₂— —CH₃, H A-26.

—CH₂— —CH₃, H A-27.

—CH₂— —CH₃, H A-28.

—CH₂— —CH₃, H A-29.

—CH₂— —CH₃, H A-30.

—CH₂— —CH₃, H A-31.

—CH₂— —CH₃, H A-32.

—CH₂— —CH₃, H A-33.

—(CH₂)₂— —CH₂— —CH₃, H A-34.

—(CH₂)₂— —CH₂— —CH₃, H A-35.

—(CH₂)₂— —CH₂— —CH₃, H A-36.

—(CH₂)₂— —CH₂— —CH₃, H A-37.

—(CH₂)₂— —CH₂— —CH₃, H A-38.

—(CH₂)₂— —CH₂— —CH₃, H A-39.

—(CH₂)₂— —CH₂— —CH₃, H A-40.

—(CH₂)₂— —CH₂— —CH₃, H A-41.

—NH—(CH₂)₂—O—

—CH₃, H A-42.

—NH—(CH₂)₂—O—

—CH₃, H A-43.

—NH—(CH₂)₂—O—

—CH₃, H A-44.

—NH—(CH₂)₂—O—

—CH₃, H A-45.

—NH—(CH₂)₂—O—

—CH₃, H A-46.

—NH—(CH₂)₂—O—

—CH₃, H A-47.

—NH—(CH₂)₂—O—

—CH₃, H A-48.

—NH—(CH₂)₂—O—

—CH₃, H A-49.

—NH—(CH₂)₂

—CH₃, H A-50.

—NH—(CH₂)₂

—CH₃, H A-51.

—NH—(CH₂)₂

—CH₃, H A-52.

—NH—(CH₂)₂

—CH₃, H A-53.

—NH—(CH₂)₂

—CH₃, H A-54.

—NH—(CH₂)₂

—CH₃, H A-55.

—NH—(CH₂)₂

—CH₃, H A-56.

—NH—(CH₂)₂

—CH₃, H A-57.

—NH—CH₂—

—CH₃, H A-58.

—NH—CH₂—

—CH₃, H A-59.

—NH—CH₂—

—CH₃, H A-60.

—NH—CH₂—

—CH₃, H A-61.

—NH—CH₂—

—CH₃, H A-62.

—NH—CH₂—

—CH₃, H A-63.

—NH—CH₂—

—CH₃, H A-64.

—NH—CH₂—

—CH₃, H A-65.

—CH₃, H A-66.

—CH₃, H A-67.

—CH₃, H A-68.

—CH₃, H A-69.

—CH₃, H A-70.

—CH₃, H A-71.

—CH₃, H A-72.

—CH₃, H A-73.

—(CH₂)₂—

—CH₃, H A-74.

—(CH₂)₂—

—CH₃, H A-75.

—(CH₂)₂—

—CH₃, H A-76.

—(CH₂)₂—

—CH₃, H A-77.

—(CH₂)₂—

—CH₃, H A-78.

—(CH₂)₂—

—CH₃, H A-79.

—(CH₂)₂—

—CH₃, H A-80.

—(CH₂)₂—

—CH₃, H A-81.

—NH—(CH₂)₂—O— —CH₂—

A-82.

—NH—(CH₂)₂—O— —CH₂—

A-83.

—NH—(CH₂)₂—O— —CH₂—

A-84.

—NH—(CH₂)₂—O— —CH₂—

A-85.

—NH—(CH₂)₂—O— —CH₂—

A-86.

—NH—(CH₂)₂—O— —CH₂—

A-87.

—NH—(CH₂)₂—O— —CH₂—

A-88.

—NH—(CH₂)₂—O— —CH₂—

A-89.

—NH—(CH₂)₂ —CH₂—

A-90.

—NH—(CH₂)₂ —CH₂—

A-91.

—NH—(CH₂)₂ —CH₂—

A-92.

—NH—(CH₂)₂ —CH₂—

A-93.

—NH—(CH₂)₂ —CH₂—

A-94.

—NH—(CH₂)₂ —CH₂—

A-95.

—NH—(CH₂)₂ —CH₂—

A-96.

—NH—(CH₂)₂ —CH₂—

A-97.

—NH—CH₂— —CH₂—

A-98.

—NH—CH₂— —CH₂—

A-99.

—NH—CH₂— —CH₂—

A-100.

—NH—CH₂— —CH₂—

A-101.

—NH—CH₂— —CH₂—

A-102.

—NH—CH₂— —CH₂—

A-103.

—NH—CH₂— —CH₂—

A-104.

—NH—CH₂— —CH₂—

A-105.

—CH₂—

A-106.

—CH₂—

A-107.

—CH₂—

A-108.

—CH₂—

A-109.

—CH₂—

A-110.

—CH₂—

A-111.

—CH₂—

A-112.

—CH₂—

A-113.

—(CH₂)₂— —CH₂—

A-114.

—(CH₂)₂— —CH₂—

A-115.

—(CH₂)₂— —CH₂—

A-116.

—(CH₂)₂— —CH₂—

A-117.

—(CH₂)₂— —CH₂—

A-118.

—(CH₂)₂— —CH₂—

A-119.

—(CH₂)₂— —CH₂—

A-120.

—(CH₂)₂— —CH₂—

A-121.

—NH—(CH₂)₂—O—

A-122.

—NH—(CH₂)₂—O—

A-123.

—NH—(CH₂)₂—O—

A-124.

—NH—(CH₂)₂—O—

A-125.

—NH—(CH₂)₂—O—

A-126.

—NH—(CH₂)₂—O—

A-127.

—NH—(CH₂)₂—O—

A-128.

—NH—(CH₂)₂—O—

A-129.

—NH—(CH₂)₂

A-130.

—NH—(CH₂)₂

A-131.

—NH—(CH₂)₂

A-132.

—NH—(CH₂)₂

A-133.

—NH—(CH₂)₂

A-134.

—NH—(CH₂)₂

A-135.

—NH—(CH₂)₂

A-136.

—NH—(CH₂)₂

A-137.

—NH—CH₂—

A-138.

—NH—CH₂—

A-139.

—NH—CH₂—

A-140.

—NH—CH₂—

A-141.

—NH—CH₂—

A-142.

—NH—CH₂—

A-143.

—NH—CH₂—

A-144.

—NH—CH₂—

A-145.

A-146.

A-147.

A-148.

A-149.

A-150.

A-151.

A-152.

A-153.

—(CH₂)₂—

A-154.

—(CH₂)₂—

A-155.

—(CH₂)₂—

A-156.

—(CH₂)₂—

A-157.

—(CH₂)₂—

A-158.

—(CH₂)₂—

A-159.

—(CH₂)₂—

A-160.

—(CH₂)₂—

A-161.

—NH—(CH₂)₂—O— —CH₂—

A-162.

—NH—(CH₂)₂—O— —CH₂—

A-163.

—NH—(CH₂)₂—O— —CH₂—

A-164.

—NH—(CH₂)₂—O— —CH₂—

A-165.

—NH—(CH₂)₂—O— —CH₂—

A-166.

—NH—(CH₂)₂—O— —CH₂—

A-167.

—NH—(CH₂)₂—O— —CH₂—

A-168.

—NH—(CH₂)₂—O— —CH₂—

A-169.

—NH—(CH₂)₂ —CH₂—

A-170.

—NH—(CH₂)₂ —CH₂—

A-171.

—NH—(CH₂)₂ —CH₂—

A-172.

—NH—(CH₂)₂ —CH₂—

A-173.

—NH—(CH₂)₂ —CH₂—

A-174.

—NH—(CH₂)₂ —CH₂—

A-175.

—NH—(CH₂)₂ —CH₂—

A-176.

—NH—(CH₂)₂ —CH₂—

A-177.

—NH—CH₂— —CH₂—

A-178.

—NH—CH₂— —CH₂—

A-179.

—NH—CH₂— —CH₂—

A-180.

—NH—CH₂— —CH₂—

A-181.

—NH—CH₂— —CH₂—

A-182.

—NH—CH₂— —CH₂—

A-183.

—NH—CH₂— —CH₂—

A-184.

—NH—CH₂— —CH₂—

A-185.

—CH₂—

A-186.

—CH₂—

A-187.

—CH₂—

A-188.

—CH₂—

A-189.

—CH₂—

A-190.

—CH₂—

A-191.

—CH₂—

A-192.

—CH₂—

A-193.

—(CH₂)₂— —CH₂—

A-194.

—(CH₂)₂— —CH₂—

A-195.

—(CH₂)₂— —CH₂—

A-196.

—(CH₂)₂— —CH₂—

A-197.

—(CH₂)₂— —CH₂—

A-198.

—(CH₂)₂— —CH₂—

A-199.

—(CH₂)₂— —CH₂—

A-200.

—(CH₂)₂— —CH₂—

A-201.

—NH—(CH₂)₂—O—

A-202.

—NH—(CH₂)₂—O—

A-203.

—NH—(CH₂)₂—O—

A-204.

—NH—(CH₂)₂—O—

A-205.

—NH—(CH₂)₂—O—

A-206.

—NH—(CH₂)₂—O—

A-207.

—NH—(CH₂)₂—O—

A-208.

—NH—(CH₂)₂—O—

A-209.

—NH—(CH₂)₂

A-210.

—NH—(CH₂)₂

A-211.

—NH—(CH₂)₂

A-212.

—NH—(CH₂)₂

A-213.

—NH—(CH₂)₂

A-214.

—NH—(CH₂)₂—O—

A-215.

—NH—(CH₂)₂

A-216.

—NH—(CH₂)₂

A-217.

—NH—CH₂—

A-218.

—NH—CH₂—

A-219.

—NH—CH₂—

A-220.

—NH—CH₂—

A-221.

—NH—CH₂—

A-222.

—NH—CH₂—

A-223.

—NH—CH₂—

A-224.

—NH—CH₂—

A-225.

A-226.

A-227.

A-228.

A-229.

A-230.

A-231.

A-232.

A-233.

—(CH₂)₂—

A-234.

—(CH₂)₂—

A-235.

—(CH₂)₂—

A-236.

—(CH₂)₂—

A-237.

—(CH₂)₂—

A-238.

—(CH₂)₂—

A-239.

—(CH₂)₂—

A-240.

—(CH₂)₂—

A-241.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-242.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-243.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-244.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-245.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-246.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-247.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-248.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₃— A-249.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-250.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-251.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-252.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-253.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-254.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-255.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-256.

—NH—(CH₂)₂— —CH₂— —(CH₂)₃— A-257.

—NH—CH₂— —CH₂— —(CH₂)₃— A-258.

—NH—CH₂— —CH₂— —(CH₂)₃— A-259.

—NH—CH₂— —CH₂— —(CH₂)₃— A-260.

—NH—CH₂— —CH₂— —(CH₂)₃— A-261.

—NH—CH₂— —CH₂— —(CH₂)₃— A-262.

—NH—CH₂— —CH₂— —(CH₂)₃— A-263.

—NH—CH₂— —CH₂— —(CH₂)₃— A-264.

—NH—CH₂— —CH₂— —(CH₂)₃— A-265.

—CH₂— —(CH₂)₃— A-266.

—CH₂— —(CH₂)₃— A-267.

—CH₂— —(CH₂)₃— A-268.

—CH₂— —(CH₂)₃— A-269.

—CH₂— —(CH₂)₃— A-270.

—CH₂— —(CH₂)₃— A-271.

—CH₂— —(CH₂)₃— A-272.

—CH₂— —(CH₂)₃— A-273.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-274.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-275.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-276.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-277.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-278.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-279.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-280.

—(CH₂)₂— —CH₂— —(CH₂)₃— A-281.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-282.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-283.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-284.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-285.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-286.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-287.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-288.

—NH—(CH₂)₂—O—

—(CH₂)₃— A-289.

—NH—(CH₂)₂—

—(CH₂)₃— A-290.

—NH—(CH₂)₂—

—(CH₂)₃— A-291.

—NH—(CH₂)₂—

—(CH₂)₃— A-292.

—NH—(CH₂)₂—

—(CH₂)₃— A-293.

—NH—(CH₂)₂—

—(CH₂)₃— A-294.

—NH—(CH₂)₂—

—(CH₂)₃— A-295.

—NH—(CH₂)₂—

—(CH₂)₃— A-296.

—NH—(CH₂)₂—

—(CH₂)₃— A-297.

—NH—CH₂—

—(CH₂)₃— A-298.

—NH—CH₂—

—(CH₂)₃— A-299.

—NH—CH₂—

—(CH₂)₃— A-300.

—NH—CH₂—

—(CH₂)₃— A-301.

—NH—CH₂—

—(CH₂)₃— A-302.

—NH—CH₂—

—(CH₂)₃— A-303.

—NH—CH₂—

—(CH₂)₃— A-304.

—NH—CH₂—

—(CH₂)₃— A-305.

—(CH₂)₃— A-306.

—(CH₂)₃— A-307.

—(CH₂)₃— A-308.

—(CH₂)₃— A-309.

—(CH₂)₃— A-310.

—(CH₂)₃— A-311.

—(CH₂)₃— A-312.

—(CH₂)₃— A-313.

—(CH₂)₂—

—(CH₂)₃— A-314.

—(CH₂)₂—

—(CH₂)₃— A-315.

—(CH₂)₂—

—(CH₂)₃— A-316.

—(CH₂)₂—

—(CH₂)₃— A-317.

—(CH₂)₂—

—(CH₂)₃— A-318.

—(CH₂)₂—

—(CH₂)₃— A-319.

—(CH₂)₂—

—(CH₂)₃— A-320.

—(CH₂)₂—

—(CH₂)₃— A-321.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-322.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-323.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-324.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-325.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-326.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-327.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-328.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₄— A-329.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-330.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-331.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-332.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-333.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-334.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-335.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-336.

—NH—(CH₂)₂— —CH₂— —(CH₂)₄— A-337.

—NH—CH₂— —CH₂— —(CH₂)₄— A-338.

—NH—CH₂— —CH₂— —(CH₂)₄— A-339.

—NH—CH₂— —CH₂— —(CH₂)₄— A-340.

—NH—CH₂— —CH₂— —(CH₂)₄— A-341.

—NH—CH₂— —CH₂— —(CH₂)₄— A-342.

—NH—CH₂— —CH₂— —(CH₂)₄— A-343.

—NH—CH₂— —CH₂— —(CH₂)₄— A-344.

—NH—CH₂— —CH₂— —(CH₂)₄— A-345.

—CH₂— —(CH₂)₄— A-346.

—CH₂— —(CH₂)₄— A-347.

—CH₂— —(CH₂)₄— A-348.

—CH₂— —(CH₂)₄— A-349.

—CH₂— —(CH₂)₄— A-350.

—CH₂— —(CH₂)₄— A-351.

—CH₂— —(CH₂)₄— A-352.

—CH₂— —(CH₂)₄— A-353.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-354.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-355.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-356.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-357.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-358.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-359.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-360.

—(CH₂)₂— —CH₂— —(CH₂)₄— A-361.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-362.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-363.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-364.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-365.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-366.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-367.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-368.

—NH—(CH₂)₂—O—

—(CH₂)₄— A-369.

—NH—(CH₂)₂—

—(CH₂)₄— A-370.

—NH—(CH₂)₂—

—(CH₂)₄— A-371.

—NH—(CH₂)₂—

—(CH₂)₄— A-372.

—NH—(CH₂)₂—

—(CH₂)₄— A-373.

—NH—(CH₂)₂—

—(CH₂)₄— A-374.

—NH—(CH₂)₂—

—(CH₂)₄— A-375.

—NH—(CH₂)₂—

—(CH₂)₄— A-376.

—NH—(CH₂)₂—

—(CH₂)₄— A-377.

—NH—CH₂—

—(CH₂)₄— A-378.

—NH—CH₂—

—(CH₂)₄— A-379.

—NH—CH₂—

—(CH₂)₄— A-380.

—NH—CH₂—

—(CH₂)₄— A-381.

—NH—CH₂—

—(CH₂)₄— A-382.

—NH—CH₂—

—(CH₂)₄— A-383.

—NH—CH₂—

—(CH₂)₄— A-384.

—NH—CH₂—

—(CH₂)₄— A-385.

—(CH₂)₄— A-386.

—(CH₂)₄— A-387.

—(CH₂)₄— A-388.

—(CH₂)₄— A-389.

—(CH₂)₄— A-390.

—(CH₂)₄— A-391.

—(CH₂)₄— A-392.

—(CH₂)₄— A-393.

—(CH₂)₂—

—(CH₂)₄— A-394.

—(CH₂)₂—

—(CH₂)₄— A-395.

—(CH₂)₂—

—(CH₂)₄— A-396.

—(CH₂)₂—

—(CH₂)₄— A-397.

—(CH₂)₂—

—(CH₂)₄— A-398.

—(CH₂)₂—

—(CH₂)₄— A-399.

—(CH₂)₂—

—(CH₂)₄— A-400.

—(CH₂)₂—

—(CH₂)₄— A-401.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-402.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-403.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-404.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-405.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-406.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-407.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-408.

—NH—(CH₂)₂—O— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-409.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-410.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-411.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-412.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-413.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-414.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-415.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-416.

—NH—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-417.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-418.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-419.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-420.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-421.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-422.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-423.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-424.

—NH—CH₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-425.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-426.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-427.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-428.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-429.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-430.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-431.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-432.

—CH₂— —(CH₂)₂—O—(CH₂)₂— A-433.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-434.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-435.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-436.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-437.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-438.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-439.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-440.

—(CH₂)₂— —CH₂— —(CH₂)₂—O—(CH₂)₂— A-441.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-442.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-443.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-444.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-445.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-446.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-447.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-448.

—NH—(CH₂)₂—O—

—(CH₂)₂—O—(CH₂)₂— A-449.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-450.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-451.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-452.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-453.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-454.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-455.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-456.

—NH—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-457.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-458.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-459.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-460.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-461.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-462.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-463.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-464.

—NH—CH₂—

—(CH₂)₂—O—(CH₂)₂— A-465.

—(CH₂)₂—O—(CH₂)₂— A-466.

—(CH₂)₂—O—(CH₂)₂— A-467.

—(CH₂)₂—O—(CH₂)₂— A-468.

—(CH₂)₂—O—(CH₂)₂— A-469.

—(CH₂)₂—O—(CH₂)₂— A-470.

—(CH₂)₂—O—(CH₂)₂— A-471.

—(CH₂)₂—O—(CH₂)₂— A-472.

—(CH₂)₂—O—(CH₂)₂— A-473.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-474.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-475.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-476.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-477.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-478.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-479.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂— A-480.

—(CH₂)₂—

—(CH₂)₂—O—(CH₂)₂—

Further particular compounds of the present invention are theaminoindane derivatives disclosed in preparation examples andphysiologically tolerated salts thereof. These include for eachpreparation example the exemplified compound as well as thecorresponding free base and any other physiologically tolerated salts ofthe free base (if the exemplified compound is a salt), or anyphysiologically tolerated salt of the free base (if the exemplifiedcompound is a free base). These further include enantiomers,diastereomers, tautomers and any other isomeric forms of said compounds,be they explicitly or implicitly disclosed.

The compounds of the formula (I) can be prepared by analogy to methodswhich are well known in the art. Suitable methods for the preparation ofcompounds of formula (I) are outlined in the following schemes.

Scheme 1 depicts the general synthesis of indanones 3 using transitionmetal-catalyzed C,C-bond formation to synthesize the indanone from adiazoprecursor. L^(x) is an ester moiety. The side chain containing X²,X³ and R⁵ can be introduced by an alkylation of the 1,3-dicarboylintermediate. Saponification of the ester moiety and decarboxylation canyield indanone 3. A detailed example is described in the experimentalsection.

In analogy to the above synthesis for compounds 14 the correspondingazetidines, wherein R⁴ and R^(4a) together with the nitrogen to whichthey are attached form an azedidine can be obtained.

The process depicted in scheme 3 is useful for obtaining aminoindanes,wherein X¹ is —O— or —S—, A² is optionally substituted alkylene, Y is—NR⁹—, and O is —S(O)₂.

In scheme 3, the variables L, R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³ are as defined herein and L² is a suitable protecting group (e.g.L²=COOEt).

The process depicted in scheme 3a is useful for obtaining indanes,wherein X¹ is —O— or —S—.

In scheme 3a, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, X²,X³ are as defined herein. One example for compound R¹—W-A¹-Q-A²-Br couldbe CH₃—SO₂—CH₂—CH₂—Br

Further protocols for the synthesis of compounds wherein W is NR⁸ aredescribed in WO2009/121872.

The process depicted in scheme 4 is useful for obtaining aminoindanes,wherein X¹ is methylene, A² is a bond, Y is —NR⁹—, and Q is —S(O)₂.

Alternatively to triflate 19, the corresponding bromide or iodide can beused to prepare compound 20.

In scheme 4, the variables L, R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³ are as defined herein, and L³ is a suitable protecting group(e.g. L³=COO^(t)Bu).

The process depicted in scheme 5 is useful for obtaining aminoindanes,wherein X¹ is optionally substituted alkylene, A² is optionallysubstituted alkylene or a bond, Y is —NR⁹—, and Q is —S(O)₂.

Instead of the trifluoroborate 66, the corresponding9-borabicyclo[3.3.1]non-9-yl derivative can be used to prepare compound26.

In scheme 5, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³, A² are as defined herein, and L³ is a suitable protecting group(e.g. L³=COO^(t)Bu).

The process depicted in scheme 6 is useful for obtaining aminoindanes,wherein X is —NR¹¹—, A² is optionally substituted alkylene, Y is —NR⁹—,and Q is —S(O)₂.

In scheme 6, the variables R¹, W, A¹, R², R³, R^(4a), R^(4b), R⁵, R⁹,X², X³, A² are as defined herein, and L⁴ and L⁴ are suitable protectinggroups.

The process depicted in scheme 7 is also useful for obtaining theaminoindanes of the invention.

1-Indanones 2 can be converted to the corresponding oximes 3 using abase followed by reaction with alkyl nitrites (e.g. isoamyl nitrite).Reduction of 3 (e.g. catalytic hydrogenation with palladium on bariumsulfate) followed by protection of the amino group (e.g. using ethylchloroformate and base) affords the N-protected alpha amino ketones 4.1,2-Addition of a suitable nucleophile (e.g. Grignard reagent) followedby elimination (e.g. treatment with methane sulfonic acid) gives theintermediate 6. Reduction of 6 (e.g. catalytic hydrogenation usingpalladium on charcoal) yields 2-amino indane 8. Deprotection of X¹ (e.g.with boron tribromide when L-X¹ is methoxy) followed by alkylation usinga suitably substituted bromide gives intermediate 9. Cleavage of theBOC-protection group (e.g. with hydrochloric acid) followed by reactionwith a functionalized sulfonyl chloride gives sulfonamide 11. Removal ofthe protection group L² (e.g. using sodium hydroxide when NH-L² is acarbamate) gives 2-amino indanes 12. These can be further functionalized(e.g. acylation followed by reduction) to give N-substituted 2-aminoindanes 13.

In scheme 7, the variables R¹, W, A¹, X¹, R², R³, R^(4a), R^(4b), R⁵,R⁹, X², X³, A² are as defined herein, and L, L² are suitable protectinggroups.

The acid addition salts of the aminoindane derivatives of formula (I)are prepared in a customary manner by mixing the free base with acorresponding acid, optionally in solution in an organic solvent, forexample a lower alcohol, such as methanol, ethanol or propanol, anether, such as methyl tert-butyl ether or diisopropyl ether, a ketone,such as acetone or methyl ethyl ketone, or an ester, such as ethylacetate.

The aminoindane derivatives of formula (II)

wherein L is an amino-protecting group, Y is NR⁹, and A², X¹, R², R³,R^(4a), R^(4b), X², X³, R⁵ are defined as above are useful asintermediates in the preparation of GlyT1 inhibitors, in particularthose of formula (I).

Suitable amino-protecting groups are well known in the art such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991.

According to a particular embodiment, L is optionally substitutedalkylcarbonyl (e.g., tert-butylcarbonyl), optionally substitutedarylcarbonyl, optionally substituted arylalkylcarbonyl (e.g.,benzylcarbonyl), optionally substituted alkoxycarbonyl (e.g.,methoxycarbonyl or tert-butyloxycarbonyl), optionally substitutedaryloxycarbonyl (e.g. phenoxycarbonyl) or optionally substitutedarylalkoxycarbonyl.

The compounds of the formula (I) are capable of inhibiting the activityof glycine transporter, in particular glycine transporter 1 (GlyT1).

The utility of the compounds in accordance with the present invention asinhibiting the glycine transporter activity, in particular GlyT1activity, may be demonstrated by methodology known in the art. Forinstance, human GlyT1c expressing recombinant hGlyT1c_(—)5_CHO cells canbe used for measuring glycine uptake and its inhibition (IC₅₀) by acompound of formula (I).

Amongst the compounds of the formula (I) those are preferred whichachieve effective inhibition at low concentrations. In particular,compounds of the formula (I) are preferred which inhibit glycinetransporter 1 (GlyT1) at a level of IC₅₀<1 μMol, more preferably at alevel of IC₅₀<0.5 μMol, particularly preferably at a level of IC₅₀<0.2μMol and most preferably at a level of IC₅₀<0.1 μMol.

The compounds of the formula (I) according to the present invention arethus useful as pharmaceuticals.

The present invention therefore also relates to pharmaceuticalcompositions which comprise an inert carrier and a compound of theformula (I).

The present invention also relates to the use of the compounds of theformula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1, and to corresponding methods of inhibitingthe glycine transporter GlyT1.

The NMDA receptor is central to a wide range of CNS processes, and itsrole in a variety of diseases in humans or other species has beendescribed. GlyT1 inhibitors slow the removal of glycine from thesynapse, causing the level of synaptic glycine to rise. This in turnincreases the occupancy of the glycine binding site on the NMDAreceptor, which increases activation of the NMDA receptor followingglutamate release from the presynaptic terminal. Glycine transportinhibitors and in particular inhibitors of the glycine transporter GlyT1are thus known to be useful in treating a variety of neurologic andpsychiatric disorders. Further, glycine A receptors play a role in avariety of diseases in humans or other species. Increasing extracellularglycine concentrations by inhibiting glycine transport may enhance theactivity of glycine A receptors. Glycine transport inhibitors and inparticular inhibitors of the glycine transporter GlyT1 are thus usefulin treating a variety of neurologic and psychiatric disorders.

The present invention thus further relates to the use of the compoundsof the formula (I) for the manufacture of a medicament for treating aneurologic or psychiatric disorder, and to corresponding methods oftreating said disorders.

According to a particular embodiment, the disorder is associated withglycinergic or glutamatergic neurotransmission dysfunction.

According to a further particular embodiment, the disorder is one ormore of the following conditions or diseases: schizophrenia or apsychotic disorder including schizophrenia (paranoid, disorganized,catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced psychotic disorder, including both thepositive and the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orcognitive impairment including age related cognitive decline; anxietydisorders including acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic attack, panicdisorder, post-traumatic stress disorder, separation anxiety disorder,social phobia, specific phobia, substance-induced anxiety disorder andanxiety due to a general medical condition; substance-related disordersand addictive behaviors (including substance-induced delirium,persisting dementia, persisting amnestic disorder, psychotic disorder oranxiety disorder; tolerance, dependence or withdrawal from substancesincluding alcohol, amphetamines, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics oranxiolytics); obesity, bulimia nervosa and compulsive eating disorders;bipolar disorders, mood disorders including depressive disorders;depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders; learning disorders,pervasive developmental disorder including autistic disorder, attentiondeficit disorders including attention-deficit hyperactivity disorder(ADHD) and conduct disorder; movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease, drug-inducedparkinsonism, postencephalitic parkinsonism, progressive supranuclearpalsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced parkinsonism (such as neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, muscular spasms and disorders associatedwith muscular spasticity or weakness including tremors; dyskinesias[including tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalised dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxymal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp and hemiplegic dystonia)];urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

According to a further particular embodiment, the disorder is pain, inparticular chronic pain and especially neuropathic pain.

Pain can be classified as acute and chronic pain. Acute pain and chronicpain differ in their etiology, pathophysiology, diagnosis and treatment.

Acute pain, which occurs following tissue injury, is self-limiting,serves as an alert to ongoing tissue damage and following tissue repairit will usually subside. There are minimal psychological symptomsassociated with acute pain apart from mild anxiety. Acute pain isnociceptive in nature and occurs following chemical, mechanical andthermal stimulation of A-delta and C-polymodal pain receptors.

Chronic pain, on the other hand, serves no protective biologicalfunction. Rather than being the symptom of tissue damage it is a diseasein its own right. Chronic pain is unrelenting and not self-limiting andcan persist for years, perhaps decades after the initial injury. Chronicpain can be refractory to multiple treatment regimes. Psychologicalsymptoms associated with chronic pain include chronic anxiety, fear,depression, sleeplessness and impairment of social interaction. Chronicnon-malignant pain is predominantly neuropathic in nature and involvesdamage to either the peripheral or central nervous systems.

Acute pain and chronic pain are caused by different neuro-physiologicalprocesses and therefore tend to respond to different types oftreatments. Acute pain can be somatic or visceral in nature. Somaticpain tends to be a well localised, constant pain and is described assharp, aching, throbbing or gnawing. Visceral pain, on the other hand,tends to be vague in distribution, paroxysmal in nature and is usuallydescribed as deep, aching, squeezing or colicky in nature. Examples ofacute pain include post-operative pain, pain associated with trauma andthe pain of arthritis. Acute pain usually responds to treatment withopioids or non-steroidal anti-inflammatory drugs.

Chronic pain, in contrast to acute pain, is described as burning,electric, tingling and shooting in nature. It can be continuous orparoxysmal in presentation. The hallmarks of chronic pain are chronicallodynia and hyperalgesia. Allodynia is pain resulting from a stimulusthat normally does not elicit a painful response, such as alight touch.Hyperalgesia is an increased sensitivity to normally painful stimuli.Primary hyperalgesia occurs immediately within the area of the injury.Secondary hyperalgesia occurs in the undamaged area surrounding theinjury. Examples of chronic pain include complex regional pain syndrome,pain arising from peripheral neuropathies, post-operative pain, chronicfatigue syndrome pain, tension-type headache, pain arising frommechanical nerve injury and severe pain associated with diseases such ascancer, metabolic disease, neurotropic viral disease, neurotoxicity,inflammation, multiple sclerosis or any pain arising as a consequence ofor associated with stress or depressive illness.

Although opioids are cheap and effective, serious and potentiallylife-threatening side effects occur with their use, most notablyrespiratory depression and muscle rigidity. In addition the doses ofopioids which can be administered are limited by nausea, emesis,constipation, pruritus and urinary retention, often resulting inpatients electing to receive suboptimal pain control rather than sufferthese distressing side-effects. Furthermore, these side-effects oftenresult in patients requiring extended hospitalisation. Opioids arehighly addictive and are scheduled drugs in many territories.

The compounds of formula (I) are particularly useful in the treatment ofschizophrenia, bipolar disorder, depression including unipolardepression, seasonal depression and post-partum depression, premenstrualsyndrome (PMS) and premenstrual dysphoric disorder (PDD), learningdisorders, pervasive developmental disorder including autistic disorder,attention deficit disorders including Attention-Deficit/HyperactivityDisorder, tic disorders including Tourette's disorder, anxiety disordersincluding phobia and post traumatic stress disorder, cognitive disordersassociated with dementia, AIDS dementia, Alzheimer's, Parkinson's,Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus andhearing impairment and loss are of particular importance.

Particular cognitive disorders are dementia, delirium, amnesticdisorders and cognitive impartment including age-related cognitivedecline.

Particular anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder and panic attack.

Particular schizophrenia or psychosis pathologies are paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder.

Particular neurologic disorders that can be treated with the compoundsof the formula (I) include in particular a cognitive disorder such asdementia, cognitive impairment, attention deficit hyperactivitydisorder.

Particular psychiatric disorders that can be treated with the compoundsof the formula (I) include in particular an anxiety disorder, a mooddisorder such as depression or a bipolar disorder, schizophrenia, apsychotic disorder.

Within the context of the treatment, the use according to the inventionof the compounds of the formula (I) involves a method. In this method,an effective quantity of one or more compounds or the formula (I), as arule formulated in accordance with pharmaceutical and veterinarypractice, is administered to the individual to be treated, preferably amammal, in particular a human being. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother drugs or drug-containing preparations.

The invention also relates to the manufacture of pharmaceuticalcompositions for treating an individual, preferably a mammal, inparticular a human being. Thus, the compounds of the formula (I) arecustomarily administered in the form of pharmaceutical compositionswhich comprise an inert carrier (e.g. a pharmaceutically acceptableexcipient) together with at least one compound according to theinvention and, where appropriate, other drugs. These compositions can,for example, be administered orally, rectally, transdermally,subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugarcoated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more carriers(excipients). Carriers (excipients) can be solid, semisolid or liquidmaterials which serve as vehicles, carriers or medium for the activecompound.

Suitable carriers (excipients) are listed in the specialist medicinalmonographs. In addition, the formulations can comprise pharmaceuticallyacceptable auxiliary substances, such as wetting agents; emulsifying andsuspending agents; preservatives; antioxidants; antiirritants; chelatingagents; coating auxiliaries; emulsion stabilizers; film formers; gelformers; odor masking agents; taste corrigents; resin; hydrocolloids;solvents; solubilizers; neutralizing agents; diffusion accelerators;pigments; quaternary ammonium compounds; refatting and overfattingagents; raw materials for ointments, creams or oils; siliconederivatives; spreading auxiliaries; stabilizers; sterilants; suppositorybases; tablet auxiliaries, such as binders, fillers, glidants,disintegrants or coatings; propellants; drying agents; opacifiers;thickeners; waxes; plasticizers and white mineral oils. A formulation inthis regard is based on specialist knowledge as described, for example,in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik undangrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy,cosmetics and related fields], 4^(th) edition, Aulendorf:ECV-Editio-Cantor-Verlag, 1996.

The compounds of formula (I) may also be suitable for combination withother therapeutic agents.

Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) with one or morefurther therapeutic agents;

ii) a pharmaceutical composition comprising a combination product asdefined in i) above and at least one carrier, diluent or excipient;

iii) the use of a combination as defined in i) above in the manufactureof a medicament for treating or preventing a disorder, disease orcondition as defined herein;

iv) a combination as defined in i) above for use in treating orpreventing a disorder, disease or condition as defined herein;

v) a kit-of-parts for use in the treatment of a disorder, disease orcondition as defined herein, comprising a first dosage form comprising acompound of formula (I) and one or more further dosage forms eachcomprising one or more further therapeutic agents for simultaneoustherapeutic administration,vi) a combination as defined in i) above for use in therapy;vii) a method of treatment or prevention of a disorder, disease orcondition as defined herein comprising administering an effective amountof a combination as defined in i) above;viii) a combination as defined in i) above for treating or preventing adisorder, disease or condition as defined herein.

The combination therapies of the invention may be administeredadjunctively. By adjunctive administration is meant the coterminous oroverlapping administration of each of the components in the form ofseparate pharmaceutical compositions or devices. This regime oftherapeutic administration of two or more therapeutic agents is referredto generally by those skilled in the art and herein as adjunctivetherapeutic administration; it is also known as add-on therapeuticadministration. Any and all treatment regimes in which a patientreceives separate but coterminous or overlapping therapeuticadministration of the compounds of formula (I) and at least one furthertherapeutic agent are within the scope of the current invention. In oneembodiment of adjunctive therapeutic administration as described herein,a patient is typically stabilized on a therapeutic administration of oneor more of the components for a period of time and then receivesadministration of another component.

The combination therapies of the invention may also be administeredsimultaneously. By simultaneous administration is meant a treatmentregime wherein the individual components are administered together,either in the form of a single pharmaceutical composition or devicecomprising or containing both components, or as separate compositions ordevices, each comprising one of the components, administeredsimultaneously. Such combinations of the separate individual componentsfor simultaneous combination may be provided in the form of akit-of-parts.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one antipsychotic agent. In a further aspect, the inventionprovides the use of compounds of formula (I) in the manufacture of amedicament for adjunctive therapeutic administration for the treatmentof a psychotic disorder in a patient receiving therapeuticadministration of at least one antipsychotic agent. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of at least oneantipsychotic agent.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of at leastone antipsychotic agent to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one antipsychotic agent in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of a psychotic disorder in a patient receivingtherapeutic administration of compounds of formula (I). The inventionfurther provides at least one antipsychotic agent for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of compounds of formula(I).

In a further aspect, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration ofcompounds of formula (I) in combination with at least one antipsychoticagent. The invention further provides the use of a combination ofcompounds of formula (I) and at least one antipsychotic agent in themanufacture of a medicament for simultaneous therapeutic administrationin the treatment of a psychotic disorder. The invention further providesa combination of compounds of formula (I) and at least one antipsychoticagent for simultaneous therapeutic administration in the treatment of apsychotic disorder. The invention further provides the use of compoundsof formula (I) in the manufacture of a medicament for simultaneoustherapeutic administration with at least one antipsychotic agent in thetreatment of a psychotic disorder. The invention further providescompounds of formula (I) for use for simultaneous therapeuticadministration with at least one antipsychotic agent in the treatment ofa psychotic disorder. The invention further provides the use of at leastone antipsychotic agent in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of a psychotic disorder. The invention further provides atleast one antipsychotic agent for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of apsychotic disorder.

In further aspects, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration of apharmaceutical composition comprising compounds of formula (I) and atleast one mood stabilising or antimanic agent, a pharmaceuticalcomposition comprising compounds of formula (I) and at least one moodstabilising or antimanic agent, the use of a pharmaceutical compositioncomprising compounds of formula (I) and at least one mood stabilising orantimanic agent in the manufacture of a medicament for the treatment ofa psychotic disorder, and a pharmaceutical composition comprisingcompounds of formula (I) and at least one mood stabilising or antimanicagent for use in the treatment of a psychotic disorder.

Antipsychotic agents include both typical and atypical antipsychoticdrugs. Examples of antipsychotic drugs that are useful in the presentinvention include, but are not limited to: butyrophenones, such ashaloperidol, pimozide, and droperidol; phenothiazines, such aschlorpromazine, thioridazine, mesoridazine, trifluoperazine,perphenazine, fluphenazine, triflupromazine, proclorperazine, andacetophenazine; thioxanthenes, such as thiothixene and chlorprothixene;thienobenzodiazepines; dibenzodiazepines; benzisoxazoles;dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines;triazine such as lamotrigine; dibenzoxazepines, such as loxapine;dihydroindolones, such as molindone; aripiprazole; and derivativesthereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs areas follows: clozapine (available under the tradename CLOZARIL®, fromMylan, Zenith Goldline, UDL, Novartis); olanzapine (available under thetradename ZYPREX®, from Lilly); ziprasidone (available under thetradename GEODON®, from Pfizer); risperidone (available under thetradename RISPERDAL®, from Janssen); quetiapine fumarate (availableunder the tradename SEROQUEL®, from AstraZeneca); haloperidol (availableunder the tradename HALDOL®, from Ortho-McNeil); chlorpromazine(available under the tradename THORAZINE®, from SmithKline Beecham(GSK)); fluphenazine (available under the tradename PROLIXIN®, fromApothecon, Copley, Schering, Teva, and American Pharmaceutical Partners,Pasadena); thiothixene (available under the tradename NAVANE®, fromPfizer); trifluoperazine(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazinedihydrochloride, available under the tradename STELAZINE®, from SmithKlein Beckman); perphenazine (available under the tradename TRILAFON®;from Schering); thioridazine (available under the tradename MELLARIL®;from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (availableunder the tradename MOBAN®, from Endo); and loxapine (available underthe tradename LOXITANE (D; from Watson). Furthermore, benperidol(Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used.Other antipsychotic drugs include promazine (available under thetradename SPARINE®), triflupromazine (available under the tradenameVESPRI N®), chlorprothixene (available under the tradename TARACTAN®),droperidol (available under the tradename INAPSINE®), acetophenazine(available under the tradename TINDAL®), proclorperazine (availableunder the tradename COMPAZINE®), methotrimeprazine (available under thetradename NOZNAN®), pipotiazine (available under the tradenamePIPOTRIL®), ziprasidone, and hoperidone.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of compounds of formula (I) to a patientreceiving therapeutic administration of at least one agent suitable forthe treatment of a neurodegenerative disorder such as Alzheimer Disease.In a further aspect, the invention provides the use of compounds offormula (I) in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease to apatient receiving therapeutic administration of compounds of formula(I). In a further aspect, the invention provides the use of at least oneagent suitable for the treatment of a neurodegenerative disorder such asAlzheimer Disease in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I). The invention furtherprovides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I).

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by simultaneoustherapeutic administration of compounds of formula (I) in combinationwith at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides the use of a combination of compounds of formula (I)and at least one agent suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in the manufacture of a medicamentfor simultaneous therapeutic administration in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of a neurodegenerative disordersuch as Alzheimer Disease for simultaneous therapeutic administration inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of compounds of formula (I) inthe manufacture of a medicament for simultaneous therapeuticadministration with at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease in the treatment ofa neurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for simultaneoustherapeutic administration with at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of at least one agent suitablefor the treatment of a neurodegenerative disorder such as AlzheimerDisease in the manufacture of a medicament for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for simultaneoustherapeutic administration with compounds of formula (I) in thetreatment of a neurodegenerative disorder such as Alzheimer Disease.

Examples of agents suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease that are useful in the presentinvention include, but are not limited to: cholinesterase inhibitors,agents targeting nicotinic or muscarinic acetylcholine receptors, NMDAreceptors, amyloid formation, mitochondrial dysfunctions, diseaseassociated calpain activity, neuroinflamation, tumor necrosis factorreceptors, NF-kappaB, peroxisome proliferator activator receptor gamma,Apolipoprotein E variant 4 (ApoE4), disease-associated increase of theHPA axis, epileptic discharges, vascular dysfunction, vascular riskfactors, and oxidative stress.

Suitable cholinesterase inhibitors which may be used in combination withthe compounds of the inventions include for example tacrine, donepezil,galantamine and rivastigmine.

Suitable NMDA receptors targeting agents which may be used incombination with the compounds of the inventions include for examplememantine.

Suitable agents affecting increased HPA axis activity which may be usedin combination with the compounds of the inventions include for exampleCRF1 antagonists or V1b antagonists.

In a further aspect therefore, the invention provides a method oftreatment of pain by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one agent suitable for the treatment of pain. In a further aspect,the invention provides the use of compounds of formula (I) in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of pain in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of pain.The invention further provides compounds of formula (I) for use foradjunctive therapeutic administration for the treatment of pain in apatient receiving therapeutic administration of at least one agentsuitable for the treatment of pain.

In a further aspect, the invention provides a method of treatment ofpain by adjunctive therapeutic administration of at least one agentsuitable for the treatment of pain to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one agent suitable for thetreatment of pain in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of pain in a patientreceiving therapeutic administration of compounds of formula (I). Theinvention further provides at least one agent suitable for the treatmentof pain for adjunctive therapeutic administration for the treatment ofpain in a patient receiving therapeutic administration of compounds offormula (I).

In a further aspect, the invention provides a method of treatment ofpain by simultaneous therapeutic administration of compounds of formula(I) in combination with at least one agent suitable for the treatment ofpain. The invention further provides the use of a combination ofcompounds of formula (I) and at least one agent suitable for thetreatment of pain in the manufacture of a medicament for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of pain for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides the use of compounds of formula (I) in the manufactureof a medicament for simultaneous therapeutic administration with atleast one agent suitable for the treatment of pain in the treatment ofpain. The invention further provides compounds of formula (I) for usefor simultaneous therapeutic administration with at least one agentsuitable for the treatment of pain in the treatment of pain. Theinvention further provides the use of at least one agent suitable forthe treatment of pain in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of pain. The invention further provides at least one agentsuitable for the treatment of pain for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of pain.

Examples of agents suitable for the treatment of pain that are useful inthe present invention include, but are not limited to: NSAIDs(Nonsteroidal Antiinflammatory Drugs), anticonvulsant drugs such ascarbamazepine and gabapentin, sodium channel blockers, antidepressantdrugs, cannabinoids and local anaesthetics.

Suitable agents used in combination with the compounds of the inventionsinclude for example celecoxib, etoricoxib, lumiracoxib, paracetamol,tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion,gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam,remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil,pethidine, diamorphine and butorphanol.

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, antidepressantagents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants, dopaminergicantidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists,5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsantagents, as well as cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of thecompounds of the invention include for example divalproex, carbamazepineand diazepam.

The following examples serve to explain the invention without limitingit.

The compounds were characterized by mass spectrometry, generallyrecorded via HPLC-MS in a fast gradient on C18-material(electrospray-ionisation (ESI) mode).

PREPARATION EXAMPLES Example I Synthesis ofN-(2-((3-benzyl-2-(amino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)sulfonamidederivatives

Synthesis of ethyl 2-diazo-4-(4-methoxyphenyl)-3-oxobutanoate (B)

Synthesis of B can be performed in analogy to the protocol in J. Org.Chem. 2001, 66, 2509-2511. At 0° C. a solution of sodium azide (2.287 g,35.2 mmol) in a minimum amount of water was added to a solution oftosylchloride (6.71 g, 35.2 mmol) in acetone (40 ml). The reactionmixture was stirred at 0° C. for 2 h. Acetone was evaporated and theremaining aqueous residue was extracted three times with Et₂O, driedover MgSO₄, filtrated and evaporated to provide the tosyl azide as aclear oil. The freshly prepared tosyl azide was dissolved in DCM (40.0ml), a mixture of commercially available ethyl4-(4-methoxyphenyl)-3-oxobutanoate (5.54 g, 23.45 mmol) andtriethylamine (4.90 ml, 35.2 mmol) in DCM (dichloromethane) was added,and stirred at room temperature over night. The product as evaporatedand purified by flash chromatography on 80 g SiO₂ using 20% EtOAc incyclohexane to obtain 4.03 g of the desired product (15.36 mM; yield:65%).

M+H⁺=263 [calculated]=262.10

Synthesis of ethyl 6-methoxy-2-oxo-2,3-dihydro-1H-indene-1-carboxylate(C)

Synthesis of C can be performed in analogy to the protocol in J. Am.Chem. Soc., 1985, 107, 196. 4.03 g (15.36 mmol) of compound 1 wasdissolved in 20 ml dry DCM and 0.05 eq rhodium (II) acetate dimerdihydrate (0.768 mmol; 358 mg) was added, and the mixture stirred atroom temperature over night. The product was filtrated, evaporated andpurified by flash chromatography on 80 g SiO₂ using 20% EtOAc incyclohexane to obtain the desired product as off white crystals (1.4 g;5.98 mmol).

M+H⁺=235 [calculated]=234.25

The ethyl 2-hydroxy-5-methoxy-1H-indene-3-carboxylate tautomer (D) wasdetermined by ^(H)-NMR.

Synthesis of ethyl1-benzyl-6-hydroxy-2,3-dihydro-1H-indene-2-ylcarbamate (E)

To a solution of ethyl6-methoxy-2-oxo-2,3-dihydro-1H-indene-1-carboxylate (100 mg, 0.427 mmol)in dry DMF (3 ml) sodium hydride (17.07 mg, 0.640 mmol) was added insmall portions, and the mixture stirred at 60° C. for 1 h. Then(bromomethyl)benzene (0.076 ml, 0.640 mmol), dissolved in a small amountof DMF, was added and the mixture was stirred at 60° C. for 4 h and thenat room temperature over night. Water was added and the red solution wasextracted twice with Et₂O. The combined organic extracts were washedwith brine, dried over MgSO₄, concentrated to dryness in vacuo andpurified by flash silica gel chromatography on 4 g SiO₂-cartridge using10% EtOAc over 20 min in cyclohexene to afford the desired compound as aclear oil. m=88.3 mg (yield: 63%)

M+H⁺=325 [calculated]=324.14

Synthesis of 1-benzyl-6-methoxy-1H-inden-2(3H)-one (F)

Compound F can be obtained by decarboxylation of E (cf. LiCl indimethylsulfoxide: Synthetic Communications (2009), 39(1), 61-69 orhydrochloric acid: WO 2008/148755 or sodium cyanide Journal of OrganicChemistry (2008), 73(7), 768-2773. or Tetrahedron (2008), 64(8),1663-1670.).

Synthesis of 1-benzyl-6-methoxy-2,3-dihydro-1H-inden-2-amine (G)

Reductive amination of compound F yields compound G (cf. Tetrahedron(2009), 65(33), 6600-6610).

Side chains containing R¹, W, A¹, Q, Y, A², X¹ and R⁹ as well assubstituents R², R³, R^(4a) and R^(4b) can be introduced in analogy tothe protocols described in WO 2009/121872.

Example II Synthesis of 1-(1-benzyl-6-methoxy-indan-2-yl)-pyrrolidineand 1-(1,1-dibenzyl-6-methoxy-indan-2-yl)-pyrrolidine derivatives

-   Bioorg. Med. Chem., 13, (2005) 6145-6150

This reaction was done in two batches. To a solution of 5-indanol 1(75.00 g; 558.96 mmol; 1.00 eq.) in N,N-dimethylformamide (417.00 ml)iodomethane (53.93 ml; 866.39 mmol; 1.55 eq.) and potassium carbonate(128.24 g; 927.88 mmol; 1.66 eq.) were added. The resulting solution wasstirred at 55° C. for 4 h under nitrogen atmosphere. The mixture wascooled to room temperature, diluted with 700 ml ether and 1.5 l water,and extracted with ether. The organic layers were washed with 5%bicarbonate, dried over MgSO₄ and concentrated. The crude product wasextracted twice with 2 N NaOH/ether, dried and concentrated in vacuo toprovide 117.37 g of an orange oil containing 2.

-   Aus. J. Chem., 1998, 51, 1167-1174

Chromium(VI) oxide (2.90 g; 29.00 mmol; 1.95 eq.) in 80% aqueous aceticacid (20.00 ml) was added slowly to an ice-cold stirred solution of 2(2.20 g; 14.84 mmol; 1.00 eq.) in acetic acid (30.00 ml) (reactionmixture colored black). The mixture was warmed to room temperature andstirred for 4.5 h. The solution was then extracted with dichloromethane,and the combined extracts were dried over magnesium sulfate andconcentrated in vacuo. 1.79 g of a beige solid containing 3 wereobtained.

-   J.O.C, 2004, 5204-5211

To a mixture of 5-methoxy-1-indanone 3 (7.70 g; 47.48 mmol; 1.00 eq.) inmethanol (200.00 ml) sodium borohydride (3.90 g; 103.09 mmol; 2.17 eq.)was added, and the mixture was refluxed for 2 h. Most of the methanolwas removed using a rotoevaporator, and 75 ml of water was added. Thismixture was extracted twice with ethyl acetate (total 225 ml). The ethylacetate extracts were combined, dried over magnesium sulfate, and thesolvent was removed at aspirator pressure to yield 6.3 g of a brown oilcontaining the corresponding alcohol of 3.

A solution of the crude 5-methoxy-1-indanol, p-toluenesulfonic acidmonohydrate (0.20 g; 1.04 mmol; 0.02 eq.) and tetrahydrofuran (150.00ml) was stirred and heated at reflux temperature for one hour. Thereaction solution was cooled, and 50 ml 5% bicarbonate was added. Mostof the THF was removed under aspirator pressure, 75 ml of water wasadded, and the mixture was extracted with diethyl ether (2×100 ml). Theether extracts were combined and dried over magnesium sulfate. Thesolvent was removed at reduced pressure to yield 5.48 g of a brown oilcontaining 4.

A solution of 4 (1.00 g; 6.84 mmol; 1.00 eq.) in 50 ml of 3:1tetrahydrofuran (37.50 ml) water (12.50 ml) and1,3-dibromo-5,5-dimethylhydantoin (0.98 g; 3.42 mmol; 0.50 eq.) wasstirred at room temperature for 30 min. Most of the THF was removed byrotaevaporation, and the product was extracted into ethyl acetate. Theethyl acetate layer was dried over magnesium sulfate and the solvent wasremoved under reduced pressure to yield a brown oil, which was dissolvedin diethyl ether but no precipitation formed:

The crude product was purified by Sepacore chromatography with DCM aseluent. 850 mg of 5 were obtained as a white solid.

-   J.O.C, 2004, 5204-5211

A mixture of potassium hydroxide (3.06 g; 54.55 mmol; 15.60 eq.) and 5(0.85 g; 3.50 mmol; 1.00 eq.) in tetrahydrofuran (50.00 ml) wasvigorously stirred at room temperature for one hour. The salts werefiltered off and washed with diethyl ether. The solvent was removed fromthe filtrate under reduced pressure to yield 540 mg of a pale yellow oilcontaining epoxide 6.

-   J.O.C, 1998, 8212-8216

A solution of 6 (300.00 mg; 1.85 mmol; 1.00 eq.) in tetrahydrofuran(2.00 ml) was added to a stirred suspension of indium(III) chloride(245.47 mg; 1.11 mmol; 0.60 eq.) in tetrahydrofuran (3.00 ml) at roomtemperature (25° C.) under nitrogen, and stirring was continued for 45min for a complete reaction (TLC). The reaction mixture was quenchedwith brine and extracted with ether. The ether extract was dried overNa₂SO₄ and evaporated to leave a crude product. The crude product waspurified by Sepacore chromatography with Et₂O/PA (1:3) as eluent. 80 mgof 7 was obtained as a white product.

810.00 mg of 7 (4.99 mmol; 1.00 eq.) were dissolved in dry methanol(10.00 ml) under nitrogen. Then pyrrolidine (0.45 ml; 5.49 mmol; 1.10eq.) was added dropwise and slowly. The mixture changed from colorlessto brown and became turbid. The mixture was stirred at 30° C. for 1.5 h.

The solvent was removed in vacuo and the residue containing 8 wasdissolved in acetonitrile (10.00 ml). At 5° C. benzylbromide (0.65 ml;5.49 mmol; 1.10 eq.) was added and the mixture was stirred for two hourat room temperature.

The crude product containing 9 and 9a was used for reduction of thedouble bond. Sodium borohydride (94.47 mg; 2.50 mmol; 0.50 eq.) andmethanol (5.00 ml) were added and the mixture was stirred at roomtemperature. (a strong gas evolution occurred). The mixture wasconcentrated in vacuo and purified by Sepacore chromatography withEtOAc/DCM (1:9)→(1:4) as eluent. 180 mg of product 10 and 150 mgdibenzylated product 10a were obtained.

NMR of 10: ¹H NMR (400 MHz, chloroform-d) δ ppm 7.20-7.27 (m, 3H) 7.08(d, J=8.21 Hz, 1H) 7.01 (d, J=6.88 Hz, 2H) 6.66 (dd, J=8.21, 2.53 Hz,1H) 5.83 (d, J=2.40 Hz, 1H) 3.50 (s, 3H) 2.74 (d, J=5.12 Hz, 3H) 2.60(d, J=6.19 Hz, 2H) 1.87 (dt, J=6.28, 3.17 Hz, 5H).

NMR of 10a: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.13-7.19 (m, 3H)7.04-7.09 (m, 3H) 6.99 (d, J=8.15 Hz, 1H) 6.84-6.94 (m, 4H) 6.71 (dd,J=8.21, 2.46 Hz, 1H) 6.14 (d, J=2.34 Hz, 1H) 3.60 (s, 3H) 3.39 (d,J=14.78 Hz, 1H) 3.02-3.13 (m, 3H) 2.92-2.99 (m, 1H) 1.73-1.83 (m, 4H).

Side chains containing R¹, W, A¹, Q, Y, A², X¹ and R⁹ as well assubstituents R² and R³ can be introduced in analogy to the protocolsdescribed in WO 2009/121872.

All final compounds have cis configuration at the indane core if nototherwise noted.

The following compounds were obtained or can be obtained using theprocedures described herein.

1

N-(2-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide 2

N-(2-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 3

N-(2-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide 4

N-(2-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide 5

N-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide 6

1-benzyl-6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2- amine 7

N-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 8

1-benzyl-6-(1- (cyclobutylsulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine 9

N-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)methyl)-11-methyl-1H-imidazole-4-sulfonamide 10

1-benzyl-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3- dihydro-1H-inden-2-amine 11

N-((3-benzyl-2-(methylamino)-2,3- dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide 12

1-benzyl-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3- dihydro-1H-inden-2-amine 13

N-(2-((3-benzyl-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 14

N-(2-((3-benzyl-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 15

N-(2-((3-benzyl-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 16

N-(2-((3-benzyl-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4- sulfonamide 17

N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 18

1-benzyl-6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H- inden-2-amine 19

N-((3-benzyl-6-fluoro-2-(methylamino)- 2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 20

1-benzyl-6-(1- (cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H-inden- 2-amine 21

N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-imidazole-4-sulfonamide22

1-benzyl-5-fluoro-N-methyl-6-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 23

N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-pyrazole-4-sulfonamide 24

1-benzyl-5-fluoro-N-methyl-6-(1-((1- methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 25

N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 26

N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 27

N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydo-1H-inden-5-yl)oxy)ethyl)-1- methyl-1H-imidazole-4-sulfonamide 28

N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- methyl-1H-pyrazole-4-sulfonamide 29

N-((2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide 30

3-(2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 31

N-((2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)methyl)-cyclobutanesulfonamide 32

3-(2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)-azetidine 33

N-((2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide 34

4-((3-(2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole 35

N-((2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)methyl-1-methyl-1H-pyrazole-4-sulfonamide 36

4-((3-(2-(azetidin-1-yl)-3-benzyl-2,3- dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole 37

N-(2-((2-(azetidin-1-yl)-3-benzyl-6- fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 38

N-(2-((2-(azetidin-1-yl)-3-benzyl-6- fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 39

N-(2-((2-(azetidin-1-yl)-3-benzyl-6- fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 40

N-(2-((2-(azetidin-1-yl)-3-benzyl-6- fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl--1H-pyrazole-4- sulfonamide 41

N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 42

3-(2-(azetidin-1-yl)-3-benzyl-6-fluoro- 2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 43

N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro- 2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 44

3-(2-(azetidin-1-yl)-3-benzyl-6-fluoro- 2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine 45

N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-imidazole-4-sulfonamide46

4-((3-(2-(azetidin-1-yl)-3-benzyl-6- fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- imidazole 47

N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-pyrazole-4-sulfonamide 48

4-((3-(2-(azetidin-1-yl)-3-benzyl-6- fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- pyrazole 49

1-cyclopropyl-N-(2-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden- 5-yl)oxy)ethyl)methanesulfonamide50

N-(2-((3-(3-fluorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 51

N-(2-((3-(3-fluorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 52

N-(2-((3-(3-fluorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4- sulfonamide 53

1-cyclopropyl-N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5- yl)methyl)methanesulfonamide 54

1-(3-fluorobenzyl)-6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2- amine 55

N-((3-(3-fluorobenzyl)-2-(methylamino)- 2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 56

6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-1-(3-fluorobenzyl)-N-methyl-2,3-dihydro- 1H-inden-2-amine 57

N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-imidazole-4-sulfonamide58

1-(3-fluorobenzyl)-N-methyl-6-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 59

N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-pyrazole-4-sulfonamide 60

1-(3-fluorobenzyl)-N-methyl-6-(1-((1- methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 61

1-cyclopropyl-N-(2-((6-fluoro-3-(3- fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)methanesulfonamide 62

N-(2-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 63

N-(2-(6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 64

N-(2-((6-fluoro-3-(3-flurobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4- sulfonamide 65

1-cyclopropyl-N-((6-fluoro-3-(3- fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5- yl)methyl)methanesulfonamide 66

6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-1-(3-fluorobenzyl)-N- methyl-2,3-dihydro-1H-inden-2-amine67

N-((6-fluoro-3-(3-fluorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 68

6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-1-(3-fluorobenzyl)-N-methyl-2,3- dihydro-1H-inden-2-amine 69

N-((6-fluoro-3-(3-fluorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4- sulfonamide 70

5-fluoro-1-(3-fluorobenzyl)-N-methyl-6- (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 71

N-((6-fluoro-3-(3-fluorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4- sulfonamide 72

5-fluoro-1-(3-fluorobenzyl)-N-methyl-6- (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 73

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 74

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 75

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 76

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4- sulfonamide 77

N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 78

3-(2-(azetidin-1-yl)-3-(3-fluorobenzyl)- 2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 79

N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)- 2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 80

3-(2-(azetidin-1-yl)-3-(3-fluorobenzyl)- 2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine 81

N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-imidazole-4-sulfonamide82

4-((3-(2-(azetidin-1-yl)-3-(3- fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- imidazole 83

N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-pyrazole-4-sulfonamide 84

4-((3-(2-(azetidin-1-yl)-3-(3- fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- pyrazole 85

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 86

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)cyclobutanesulfonamide 87

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- imidazole-4-sulfonamide 88

N-(2-((2-(azetidin-1-yl)-3-(3- fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- pyrazole-4-sulfonamide 89

N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5- yl)methyl)-1-cyclopropylmethanesulfonamide 90

3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5- yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 91

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5- yl)methyl)cyclobutanesulfonamide92

3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine 93

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4- sulfonamide 94

4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- imidazole 95

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5- yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide 96

4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- pyrazole 97

N-(2-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 98

N-(2-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 99

N-(2-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 100

N-(2-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4- sulfonamide 101

N-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 102

1-(3-chlorobenzyl)-6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2- amine 103

N-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 104

1-(3-chlorobenzyl)-6-(1- (cyclobutanesulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine 105

N-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4- sulfonamide 106

1-(3-chlorobenzyl)-N-methyl-6-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 107

N-((3-(3-chlorobenzyl)-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4- sulfonamide 108

1-(3-chlorobenzyl)-N-methyl-6-(1-((1- methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 109

N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide 110

N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 111

N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 112

N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4- sulfonamide 113

N-((3-(3-chlorobenzyl)-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 114

1-(3-chlorobenzyl)-6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H- inden-2-amine 115

N-((3-(3-chlorobenzyl)-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 116

1-(3-chlorobenzyl)-6-(1- (cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H-inden- 2-amine 117

N-((3-(3-chlorobenzyl)-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4- sulfonamide 118

1-(3-chlorobenzyl)-5-fluoro-N-methyl-6- (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-5-amine 119

N-((3-(3-chlorobenzyl)-6-fluoro-2- (methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4- sulfonamide 120

1-(3-chlorobenzyl)-5-fluoro-N-methyl-6- (1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro- 1H-inden-2-amine 121

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 122

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 123

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4- sulfonamide 124

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-methyl-1H-pyrazole-4- sulfonamide 125

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 126

3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)- 2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 127

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)- 2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide 128

3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)- 2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine 129

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-imidazole-4-sulfonamide130

4-((3-(2-(azetidin-1-yl)-3-(3- chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- imidazole 131

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- methyl-1H-pyrazole-4-sulfonamide132

4-((3-(2-(azetidin-1-yl)-3-(3- chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H- pyrazole 133

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 134

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)cyclobutanesulfonamide 135

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- imidazole-4-sulfonamide 136

N-(2-((2-(azetidin-1-yl)-3-(3- chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- pyrazole-4-sulfonamide 137

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5- yl)methyl)-1-cyclopropylmethanesulfonamide 138

3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 139

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5- yl)methyl)cyclobutanesulfonamide 140

3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)-1- (cyclobutylsulfonyl)azetidine 141

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)6-fluoro-2,3-dihydro-1H-inden-5- yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide 142

4-((3-(2-(azetidin-1-yl)-3-(3- chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1- methyl-1H-imidazole 143

N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5- yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide 144

4-((3-(2-(azetidin-1-yl)-3-(3- chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1- methyl-1H-pyrazole 145

1-cyclopropyl-N-(2-((2-(methylamino)- 3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)methanesulfonamide 146

N-(2-((2-(methylamino)-3-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)cyclobutanesulfonamide 147

1-methyl-N-(2-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1H-imidazole-4- sulfonamide 148

1-methyl-N-(2-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1H-pyrazole-4- sulfonamide 149

1-cyclopropyl-N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro- 1H-inden-5-yl)methyl)methanesulfonamide 150

6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3- yl)-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-2-amine 151

N-((2-(methylamino)-3-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5- yl)methyl)cyclobutanesulfonamide 152

6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-N-methyl-1-(3-(trifluoromethyl)benzyl)- 2,3-dihydro-1H-inden-5-amine 153

1-methyl-N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1H-imidazole-4- sulfonamide 154

N-methyl-6-(1-((1-methyl-1H-imidazol- 4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-2-amine 155

1-methyl-N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1H-pyrazole-4- sulfonamide 156

N-methyl-6-(1-((1-methyl-1H-pyrazole-4- yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-2-amine 157

1-cyclopropyl-N-(2-((6-fluoro-2- (methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)oxy)ethyl)methanesulfonamide 158

N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 159

N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- imidazole-4-sulfonamide 160

N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- pyrazole-4-sulfonamide 161

1-cyclopropyl-N-((6-fluoro-2- (methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)methanesulfonamide 162

6-(1- ((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-1-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine 163

6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-1-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine 164

6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-5- fluoro-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-2-amine 165

N-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide 166

5-fluoro-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro- 1H-inden-2-amine 167

N-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide 168

5-fluoro-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-2-amine 169

N-(2-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 170

N-(2-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5- yl)oxy)ethyl)cyclobutanesulfonamide 171

N-(2-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- imidazole-4-sulfonamide 172

N-(2-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- pyrazole-4-sulfonamide 173

N-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1- cyclopropylmethanesulfonamide 174

3-(2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)-1- ((cyclopropylmethyl)sulfonyl)azetidine 175

N-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5- yl)methyl)cyclobutanesulfonamide 176

3-(2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)-1- (cyclobutylsulfonyl)azetidine 177

N-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl-1-methyl-1H- imidazole-4-sulfonamide 178

4-((3-(2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1- methyl-1H-imidazole 179

N-((2-(azetidin-1-yl)-3-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H- pyrazole-4-sulfonamide 180

4-((3-(2-(azetidin-1-yl)-3-(3- (trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1- methyl-1H-pyrazole 181

N-(2-((2-(azetidin-1-yl)-3-(3- trifluoromethyl)benzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1- cyclopropylmethanesulfonamide 182

N-(2-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)oxy)ethyl)cyclobutanesulfonamide 183

N-(2-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- imidazole-4-sulfonamide 184

N-(2-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H- pyrazole-4-sulfonamide 185

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide 186

3-(2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine 187

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)methyl)cyclobutanesulfonamide 188

3-(2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)-1-(cyclobutylsulfonyl)azetidine 189

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide 190

4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1- methyl-1H-imidazole 191

N-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H- inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide 192

4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1- methyl-1H-pyrazole

Example 193N-(2-(2-Amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

193.12-(Hydroxyimino)-6-methoxy-2,3-dihydro-1H-inden-1-one

To a solution of 6-methoxy-1-indanone (15 g, 92 mmol) in diethyl ether(200 ml) was added concentrated hydrochloric acid (15 ml) followed byisoamylnitrile (14.86 ml, 111 mmol) and the reaction mixture was stirredat room temperature for 2 h. The yellow precipitate was filtered, washedwith diethyl ether and dried over magnesium sulphate to obtain thedesired product 2-(hydroxyimino)-6-methoxy-2,3-dihydro-1H-inden-1-one asa yellow solid. m=16.76 g (95%)

ESI-MS [M+H⁺]=192 Calculated for C₁₀H₉NO₃=191

193.22-Amino-6-methoxy-2,3-dihydro-1H-inden-1-one hydrochloride

2-(Hydroxyimino)-6-methoxy-2,3-dihydro-1H-inden-1-one (18.28 g, 96 mmol)and 5% Pd on barium sulfate (0.509 g, 4.78 mmol) in a solvent mixture ofmethanol (200 ml), Water (100 ml) and 12N hydrochloric acid (20 ml) washydrogenated at room temperature for 4d.

Filtered and washed with methanol until a grey precipitate remains(2-amino-6-methoxy-2,3-dihydro-1H-inden-1-one hydrochloride). m=15.4 g(75%)

ESI-MS [M+H⁺]=192 Calculated for C₁₀H₁₂ClNO₂=213

193.3 Ethyl 6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate

To a suspension of 2-amino-6-methoxy-2,3-dihydro-1H-inden-1-onehydrochloride (15.4 g, 72.1 mmol) in dichloromethane was added ethylchloroformate (10.38 ml, 108 mmol) followed by dropwise addition of asolution of diisopropylamine (25.2 ml, 144 mmol) in 10 mldichloromethane. The reaction mixture was stirred at room temperatureover night. Added 1N hydrochloric acid, diluted with dichloromethane,separated organic layer and the aqueous layer was extracted twice withdichloromethane. The combined organic layers were washed subsequentlywith water, sodium bicarbonate and brine, dried, filtered and evaporatedto obtain the product (ethyl6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate) as a purple solid.m=16.4 g (95%)

ESI-MS [M+H⁺]=250 Calculated for C₁₃H_(15N)O₄=249

193.4 Ethyl1-benzyl-1-hydroxy-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate

To ice cold 2M benzylmagnesium chloride in tetrahydrofuran (6.14 ml,12.28 mmol) was added dropwise a solution of ethyl6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-ylcarbamate (1.02 g. 4.09 mmol)in tetrahydrofuran (30 ml) and stirred over night, while the reactionmixture was allowed to warm up to room temperature. The reaction mixturewas quenched with sat. ammonium chloride and the organic layer wasevaporated. The residue was extracted twice with dichloromethane and thecombined organic layers were washed subsequently with sodium bicarbonateand brine, dried, filtered and evaporated to obtain a dark gooey oil,that was purified by flash silica gel chromatography on 12 g SiO₂—cartridge using 30% ethyl acetate in cyclohexane to afford the desiredethyl 1-benzyl-1-hydroxy-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate asa brown grease. m=1.07 g (77%)

ESI-MS [M+H⁺]=342 and ESI-MS [M−H₂O+H⁺]=324 Calculated for C₂₀H₂₃NO₄=341

193.5(Z)-Ethyl1-benzylidene-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate

To a solution of ethyl1-benzyl-1-hydroxy-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate (184 mg,0.539 mmol) in toluene (4 ml) was added methanesulfonic acid (3.50 μl,0.054 mmol) and stirred at room temperature over night. The solution wasevaporated, re-dissolved in dichloromethane, washed with sodiumbicarbonate and brine, dried over sodium bicarbonate and evaporated todryness to obtain the desired (Z)-ethyl1-benzylidene-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate as a paleyellow oil. m=154 mg (88%)

ESI-MS [M+H⁺]=324 Calculated for C₂₀H₂₁NO₃=323

193.6cis-Ethyl 1-benzyl-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate

A suspension of (E)-ethyl1-benzylidene-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate (1.24 g, 3.83mmol) and 10% Pd/C (0.020 g, 0.192 mmol) in methanol (20 ml) washydrogenated at room temperature for 3 h. Filtered and evaporated toobtain the product as an off white solid (cis/trans mixture). m=1.21 g(97%)

ESI-MS [M+H⁺]=326 Calculated for C₂₀H₂₃NO₃=325

Recrystallisation from methanol afford the pure cis-ethyl1-benzyl-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate

193.7-Ethyl 1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate

To a stirred and cooled (−10° C.) solution of ethyl1-benzyl-6-methoxy-2,3-dihydro-1H-inden-2-ylcarbamate (668 mg, 2.053mmol) in dichloromethane (15 ml) under argon was added dropwise 1Mtribromoborane (6.16 ml, 6.16 mmol) and stirred over night while thereaction mixture was allowed to warm up to room temperature. Poured intoice water, diluted with dichloromethane, separated organic layer and theaqueous layer was extracted twice with dichloromethane. The combinedorganic layers were washed subsequently with water, sodium bicarbonateand brine, dried, filtered and evaporated to obtain ethyl1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate as a brown solid.m=620 mg (97%)

ESI-MS [M+H⁺]=312 Calculated for C₁₉H₂₁NO₃=311

193.8 Ethyl6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate

A suspension of ethyl1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (620 mg, 1.991mmol) and caesium carbonate (1298 mg, 3.98 mmol) in acetonitrile (15 ml)was stirred at 80° C. under argon for 1 h, cooled down to 50° C. andtert-butyl 2-bromoethylcarbamate (669 mg, 2.99 mmol) dissolved inacetonitrile was slowly added. Stirred at 80° C. for 2 h. Evaporatedacetonitrile, re-dissolved in dichloromethane, washed with water,co-extracted aqueous layer twice with dichloromethane and the combinedorganic layers were dried, filtered and evaporated and purified by flashsilica gel chromatography on 40 g SiO₂-cartridge using 30% ethyl acetatein cyclohexane to afford the titled compound as a brown oil. m=624 mg

ESI-MS [M+Na⁺]=477 Calculated for C₂₆H₃₄N₂O₅=455

Formic acid (5 mL, 130 mmol) was added and stirred at room temperatureuntil TLC showed completion of the reaction. Added 2N sodium hydroxideand extracted twice with dichloromethane, dried, filtered and evaporatedto obtain ethyl6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate as a paleyellow grease. m=439 mg (90%)

ESI-MS [M+H⁺]=355 Calculated for C₂₁H₂₆N₂O₃=354

193.9-Ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate

To a stirred solution of ethyl6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate (439 mg,1.239 mmol) in dry dichloromethane (10 ml) was added4-dimethylaminopyridine (0.230 ml, 1.858 mmol) followed by1-methyl-1H-imidazole-4-sulfonyl chloride (268 mg, 1.486 mmol). Thereaction mixture was stirred at room temperature over night. Addeddichloromethane and washed twice with 1N hydrochloric acid, Thecollected organic layers were washed with water, sodium bicarbonate andbrine, dried, filtered and evaporated to obtain the titled crude productas a brown grease, that was purified by flash silica gel chromatographyon 12 g SiO₂-cartridge using 5% methanol in dichloromethane to affordethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamateas an orange oil. m=192 mg (31%)

ESI-MS [M+H⁺]=499 Calculated for C₂₅H₃₀N₄O₅S=498

193.10N-(2-(2-Amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

To ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate(192 mg, 0.385 mmol) was added 2N potassium hydroxide in ethanol (10 mL,20.00 mmol) and microwave at 100° C. for 1 h. Washed with 50% brine andextracted with dichloromethane. The combined org. layers were washedwith brine, dried, filtered and evaporated to obtain the desiredN-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas an orange grease. m=142 mg (63%)

ESI-MS [M+H⁺]=427 Calculated for C₂₂H₂₆N₄O₃S=426

Example 194cis-N-(2-(2-Amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

This compound was synthesized in the same manner described for thecompound of example 193 using5-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-one instead of6-methoxy-1-Indanone.

ESI-MS [M+H⁺]=445 Calculated for C₂₂H₂₅FN₄O₃S=444

Example 195 Ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate

To a stirred solution of ethyl6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate (439 mg,1.239 mmol; see example 193.8) in dry dichloromethane (10 ml) was added4-dimethylaminopyridine (0.230 ml, 1.858 mmol) followed by1-methyl-1H-imidazole-4-sulfonyl chloride (268 mg, 1.486 mmol). Thereaction mixture was stirred at room temperature for 1 h. Addeddichloromethane and washed twice with 1N hydrochloric acid. Thecollected organic layers were washed with water, sodium bicarbonate andbrine, dried, filtered and evaporated to obtain the titled crude productas a brown grease, that was purified by flash silica gel chromatographyon 12 g SiO₂-cartridge using 5% methanol in dichloromethane to affordthe desired product ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamateas an orange oil. m=192 mg (31%)

ESI-MS [M+H⁺]=499 Calculated for C₂₅H₃₀N₄O₅S=498

Example 196 Ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-2-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate

To a stirred solution of ethyl6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate (44.7 mg,0.126 mmol; see example 193.8) in dry dichloromethane (2 ml) was added4-dimethylaminopyridine (18.49 mg, 0.151 mmol) followed by1-methyl-1H-imidazole-2-sulfonyl chloride (22.78 mg, 0.126 mmol). Thereaction mixture was stirred at room temperature for 1 h. Addeddichloromethane and washed twice with 1N hydrochloric acid. Thecollected organic layers were washed with water, sodium bicarbonate andbrine, dried, filtered and evaporated to obtain ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-2-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamateas a white foam. m=60 mg (95%)

ESI-MS [M+H⁺]=499 Calculated for C₂₅H₃₀N₄O₅S=498

Example 197N-{2-[(2-Amino-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy]ethyl}-1-methyl-1H-imidazole-4-sulfonamidehydrochloride

To ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate(33 mg, 0.066 mmol; see example 195) was added 2N potassium hydroxide inethanol (4 mL, 8.00 mmol) and stirred at 90° C. for 1 h. 50% brine wasadded and extracted twice with dichloromethane. The combined organiclayers were washed with brine, dried, filtered and evaporated to obtaina clear oil m=27.3 mg. Added 2N hydrochloric acid/diethyl ether andstirred at room temperature for 2 h, filtered, washed with diethyl etherand dried to obtain the desired product as a white solid. m=8.6 mg (28%)

ESI-MS [M−HCl+H⁺]=427 Calculated for C₂₂H₂₇ClN₄O₃S=463

Example 198N-(2-(2-Amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-2-sulfonamidehydrochloride

To ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-2-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate(26.7 mg, 0.054 mmol; see example 196) was added 2N potassium hydroxidein ethanol (4 mL, 8.00 mmol) and stirred at 90° C. for 1 h. 50% brinewas added and extracted twice with dichloromethane. The combined organiclayers were washed with brine, dried, filtered and evaporated to obtaina clear oil. Added 2N hydrochloric acid/diethyl ether and stirred atroom temperature for 2 h, filtered, washed with diethyl ether and driedto obtainN-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-2-sulfonamidehydrochloride as a white solid. m=20.2 mg (54%)

ESI-MS [M−HCl+H⁺]=427 Calculated for C₂₂H₂₇ClN₄O₃S=463.

Example 199N-(2-(3-Benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

To ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate(23.8 mg, 0.048 mmol; see example 195) in tetrahydrofuran (1 ml) wasadded lithium aluminium hydride in tetrahydrofuran (0.143 ml, 0.143mmol) and the reaction mixture was refluxed for 2 h. Cooled down to roomtemperature and a 2N sodium hydroxide was slowly added and extractedtwice with dichloromethane, washed with sodium bicarbonate and brine,dried, filtered and evaporated to obtain the crude material as whitesolid, that was purified by flash silica gel chromatography on 4 gSiO₂-cartridge using 10% methanol in dichloromethane over 25 min toaffordN-(2-(3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a clear glass. m=6.4 mg (23%)

ESI-MS [M+H⁺]=441 Calculated for C₂₃H₂₈N₄O₃S=440

Example 200cis-N-(2-(3-Benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

To ethylcis-1-benzyl-5-fluoro-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate(45.3 mg, 0.088 mmol) in tetrahydrofuran (1 ml) was added lithiumaluminium hydride 1M in tetrahydrofuran (0.263 ml, 0.263 mmol) and thereaction mixture was refluxed for 2 h. Cooled down to room temperatureand added a mixture of 0.5N potassium hydroxide (1 ml) and water (7 ml),filtered over Celite, washed with tetrahydrofuran and the Celite Filtercake was poured into tetrahydrofuran, refluxed for 30 min, and againfiltered over Celite. The combined organic layers were evaporated,re-dissolved in dichloromethane, washed with sodium bicarbonate andbrine, dried over magnesium sulfate, filtered and evaporated to obtain apale yellow oil, that was purified by flash silica gel chromatography on4 g SiO₂-cartridge using 10% methanol in dichloromethane to obtaincis-N-(2-(3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a pale yellow oil. m=14.2 mg (35%)

ESI-MS [M+H⁺]=459 Calculated for C₂₃H₂₇FN₄O₃S=458

Example 201cis-N-(2-{[2-(Azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide

ToN-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(17.9 mg, 0.040 mmol) was added 1,3-dibromopropane (4.904, 0.048 mmol)and potassium carbonate (6.12 mg, 0.044 mmol) in water (1 mL)+5 dropacetonitrile were added. Microwave at 120° C. for 20 min. Evaporatedacetonitrile, re-dissolved in dichloromethane and extracted with waterand brine, dried over sodium bicarbonate, filtered and evaporated toobtain the crude product, that was purified by flash silica gelchromatography on 4 g SiO₂-cartridge using 10% methanol indichloromethane to affordcis-N-(2-{[2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a clear glass. m=4.0 mg (20%)

ESI-MS [M+H⁺]=485 Calculated for C₂₅H₂₉FN₄O₃S=484

Example 202N-(2-(2-(Azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

ToN-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(35.4 mg, 0.083 mmol; see example 193), 1,3-dibromopropane and potassiumcarbonate (12.62 mg, 0.091 mmol) in water (1 mL)+1 drop acetonitrilewere added. Microwave at 120° C. for 20 min. Evaporated acetonitrile,re-dissolved in dichloromethane and extracted with water and brine,dried over sodium bicarbonate, filtered and evaporated to obtain thecrude product and was purified by flash silica gel chromatography on 4 gSiO₂-cartridge using 10% methanol in dichloromethane to obtainN-(2-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a clear glass. m=3.1 mg (8%)

ESI-MS [M+H⁺]=467 Calculated for C₂₅H₃₀N₄O₃S=466

Example 203N-(2-(3-Benzyl-6-fluoro-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

ToN-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(20.7 mg, 0.047 mmol), 10 equivalents 1-bromo-3-chloro-2-methylpropaneand potassium carbonate (70.8 mg) in water (1 mL)+1 drop acetonitrilewere added. Microwave at 120° C. Evaporated acetonitrile, re-dissolvedin dichloromethane and extracted with water and brine, dried over sodiumbicarbonate, filtered and evaporated to obtain the crude product and waspurified by flash silica gel chromatography on 4 g SiO₂-cartridge using10% methanol in dichloromethane to affordN-(2-(3-benzyl-6-fluoro-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a clear glass m=2.0 mg (8.6%)

ESI-MS [M+H⁺]=499 Calculated for C₂₆H₃₁FN₄O₃S=498

Example 204N-(2-(3-Benzyl-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

ToN-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(43 mg, 0.101 mmol; see example 193), 1-bromo-3-chloro-2-methylpropane(0.093 mL, 0.807 mmol) and potassium carbonate (111 mg, 0.807 mmol) inwater (1 mL) +1 drop acetonitrile were added. Microwave at 120° C. for40 min. Evaporated acetonitrile, re-dissolved in dichloromethane andextracted with water and brine, dried over sodium bicarbonate, filteredand evaporated to obtain the crude product as a brown oil, that waspurified by flash silica gel chromatography on 4 g SiO₂-cartridge using10% methanol in dichloromethane to affordN-(2-(3-benzyl-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a yellow oil. m=4.9 mg (10%)

ESI-MS [M+H⁺]=481 Calculated for C₂₆H₃₂N₄O₃S=480

Example 205N-(2-{[3-Benzyl-2-(3,3-dimethylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide

205.1:N-(1-Benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamide

To a solution ofN-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(40.5 mg, 0.095 mmol; see example 193) in dry dichloromethane (2 ml)containing diisopropylamine (0.025 ml, 0.142 mmol) and under argon wasadded a solution of 3-chloropivaloyl chloride (0.019 ml, 0.142 mmol) indichloromethane and stirred at room temperature over night. Added 0.5Mhydrochloric acid and extracted with dichloromethane, co extractedaqueous layer with dichloromethane and the combined organic layers werewashed with sodium bicarbonate and brine, dried over sodium bicarbonate,filtered and evaporated to obtain the desiredN-(1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamideas yellow oil. m=51 mg (quant.) that was used without furtherpurification for the next steps.

ESI-MS [M+H⁺]=545 Calculated for C₂₇H₃₃ClN₄O₄S=544

205.2:N-(2-(3-Benzyl-2-(3-chloro-2,2-dimethylpropylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

To a solution ofN-(1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamide(51.8 mg, 0.095 mmol) in dry tetrahydrofuran (1 ml) was added 2M boranedimethyl complex (0.143 ml, 0.285 mmol) and stirred at 60° C. for 6 hand at room temperature over night. Quenched by dropwise addition of0.5N hydrochloric acid and refluxed for an other 2 h, the solution wassaponified with sodium hydroxide and extracted three times withdichloromethane, dried, filtered and evaporated to obtain the crudeproduct (m=53 mg) as a yellow oil that was purified by flash silica gelchromatography on 4 g SiO2-cartridge using 5% methanol indichloromethane to afford the titled compoundN-(2-(3-benzyl-2-(3-chloro-2,2-dimethylpropylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a pale yellow oil. m=17.7 mg (35%)

ESI-MS [M+H⁺]=531 Calculated for C₂₇H₃₅ClN₄O₃S=530.

205.3:N-(2-(3-Benzyl-2-(3,3-dimethylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

DissolvedN-(2-(3-benzyl-2-(3-chloro-2,2-dimethylpropylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(17.7 mg, 0.033 mmol in dry acetonitrile (2.000 ml) and added sodiumbicarbonate (5.60 mg, 0.067 mmol). Microwave at 70° C. for 2 h.Evaporated solvents and re-dissolved in dichloromethane, washed withwater and brine, dried over magnesium sulfate, filtered and evaporatedto obtain the crude product as clear white oil, that was purified bycolumn chromatography on 1.5×2.5 cm SiO₂ using 5% methanol indichloromethane to affordN-(2-(3-benzyl-2-(3,3-dimethylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a white solid. m=1.7 mg (10%)

ESI-MS [M+H⁺]=495 Calculated for C₂₇H₃₄N₄O₃S=494

Example 206cis-N-(2-{[3-Benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide

To a solution ofcis-N-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(44.3 mg, 0.100 mmol; see example 194) and in dry ethanol (2 ml) wasadded 2-(chloromethyl)-2-methoxirane (9.65 μl, 0.100 mmol) and theresulting mixture was microwave at 70° C. for 1 h. The reaction mixturewas concentrated under reduced pressure and the residue was stirred inacetone (2.000 ml) for 30 min. The crude product was purified by flashsilica gel chromatography on 4 g SiO₂-cartridge using 5% methanol indichloromethane to afford the desired productcis-N-(2-(3-benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a clear oil. m=20.5 mg (40%)

ESI-MS [M+H⁺]=515 Calculated for C₂₆H₃₁FN₄O₄S=514

Example 207N-(2-(3-Benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-N,1-dimethyl-1H-imidazole-4-sulfonamide

At 0° C. sodium hydride (0.589 mg, 0.022 mmol) was added to a solutionofcis-N-(2-(3-benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(9.1 mg, 0.018 mmol; see example 206) in dry tetrahydrofuran (1 ml). Theobtained suspension was stirred for 30 min at 0° C. and 1 h at roomtemperature. After dropwise addition of methyl iodide (1.216 μl, 0.019mmol) the reaction mixture was stirred for 5 h and poured on a mixtureof sat. ammonium chloride/ethyl acetate. The organic layer was separatedand the aqueous layer washed twice with ethyl acetate. The combinedorganic layers were washed with sat. ammonium chloride, water and brine,dried over magnesium sulfate, filtered and evaporated to obtain thecrude product as a pale yellow oil, that was purified on 1.5×5 cmSiO₂-column using 5% methanol in dichloromethane to affordN-(2-(3-benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-N,1-dimethyl-1H-imidazole-4-sulfonamideas clear oil. m=3.1 mg (33%)

ESI-MS [M+H⁺]=529 Calculated for C₂₇H₃₃FN₄O₄S=528

Example 208 Ethyl1-benzyl-5-fluoro-6-((1-methyl-1H-imidazole-4-sulfonamido)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate

Example 208.13-Benzyl-2-(ethoxycarbonylamino)-6-fluoro-2,3-dihydro-1H-inden-5-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

Perfluorobutanesulfonyl fluoride (0.392 ml, 2.004 mmol) and Et₃N (0.419ml, 3.01 mmol) in abs. dichloromethane (10 ml) was added dropwise to theintermediate ethyl1-benzyl-5-fluoro-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (330 mg,1.002 mmol), dissolved in dichloromethane and stirred at roomtemperature over night. Evaporated and purified by flash silica gelchromatography on 12 g SiO₂-cartridge using dichloromethane to afford3-benzyl-2-(ethoxycarbonylamino)-6-fluoro-2,3-dihydro-1H-inden-5-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonateas a yellow product. M=389 mg (63%)

ESI-MS [M+H⁺]=613 Calculated for C₂₃H₁₉F₁₀NO₅S=611

Example 208.2 Ethyl1-benzyl-6-cyano-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate

Dimethylformamide was degased with argon for 15 min then3-benzyl-2-(ethoxycarbonylamino)-6-fluoro-2,3-dihydro-1H-inden-5-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate(389 mg, 0.636 mmol) was added followed by Pd₂(dba)₃ (117 mg, 0.127mmol), 1,1-bis(diphenylphosphino)ferrocene (78 mg, 0.140 mmol) and zincdust (16.64 mg, 0.254 mmol). Heated up to 100° C. for 15 min and thenzinc cyanide (44.8 mg, 0.382 mmol) was added. Heated up to 100° C. foranother 2 h. Filtered over Celite, diluted with ethyl acetate andevaporated to obtain a brown oil, that was purified by flash silica gelchromatography on 4 g SiO₂-cartridge using 20% ethyl acetate incyclohexane to afford the titled compound ethyl1-benzyl-6-cyano-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate as a palebrown oil. m=182 mg (85%)

ESI-MS [M+H⁺]=339 Calculated for C₂₀H₁₉FN₂O₂=338

Example 208.3 Ethyl6-(aminomethyl)-1-benzyl-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate

To a solution of ethyl1-benzyl-6-cyano-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate (182 mg,0.538 mmol) in methanol (5 ml) containing cobalt(II) chloridehexahydrate (256 mg, 1.076 mmol) was added sodium borohydride (203 mg,5.38 mmol) in small portions with caution to control the evolution ofhydrogen and the exothermic reaction (approximately 1 h). The reactionmixture was stirred at room temperature for 10 min and carefullyquenched by addition of 12N hydrochloric acid until the blackprecipitate was dissolved. The reaction mixture was carefully madealkaline with concentrated ammonia and extracted with ethyl acetate,dried, filtered and evaporated to leave the crude product ethyl6-(aminomethyl)-1-benzyl-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate apale brown oil. m=184 mg (quant.)

ESI-MS [M+H⁺]=343 Calculated for C₂₀H₂₃FN₂O₂=342

-   J. Med. Chem, 2005, Vol. 48, p. 3030

Example 208.4 Ethyl1-benzyl-5-fluoro-6-((1-methyl-1H-imidazole-4-sulfonamido)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate

To a stirred solution ofethyl-6-(aminomethyl)-1-benzyl-5-fluoro-2,3-dihydro-1H-inden-2-ylcarbamate(184 mg, 0.376 mmol) in dichloromethane (3 ml) was added4-dimethylaminopyridine (68.9 mg, 0.564 mmol) followed by1-methyl-1H-imidazole-4-sulfonyl chloride (102 mg, 0.564 mmol). Thereaction mixture was stirred at room temperature for 1 h. Addeddichloromethane and washed 2×1 N hydrochloric acid. The collected org.layers were washed with water, sodium bicarbonate and brine, dried,filtered and evaporated to obtain the titled crude product as a paleyellow grease, that was purified by flash silica gel chromatography on 4g SiO₂-cartridge using 5% MeOH in dichloromethane to afford the desiredproduct ethyl1-benzyl-5-fluoro-6-((1-methyl-1H-imidazole-4-sulfonamido)methyl)-2,3-dihydro-1H-inden-2-ylcarbamateas a clear glass. m=73 mg (40%)

ESI-MS [M+H⁺]=487 Calculated for C₂₄H₂₇FN₄O₄S=486

Example 209cis-N-{[3-Benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide(a) andtrans-N-{[3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide(b)

To ethyl1-benzyl-5-fluoro-6-((1-methyl-1H-imidazole-4-sulfonamido)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate(37.5 mg, 0.077 mmol; see example 208) in tetrahydrofuran (1 ml) wasadded lithium aluminium hydride 1M in tetrahydrofuran (0.231 ml, 0.231mmol) and the reaction mixture was refluxed for 2 h. Cooled down to roomtemperature. Added 0.5N potassium hydroxide (1 ml) and water (7 ml),filtered over Celite, washed with tetrahydrofuran and the Celite filtercake was poured into tetrahydrofuran, refluxed for 30 min, and filteredagain over Celite. The combined organic layers were evaporated,re-dissolved in dichloromethane, washed with sodium bicarbonate andbrine, dried over MgSO₄, filtered and evaporated to obtain the crudeproduct as a pale yellow oil that was purified by flash silica gelchromatography on 4 g SiO₂-cartridge using 10% methanol indichloromethane to obtained the desired productscis-N-{[3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide(7.9 mg, 24%) andtrans-N-{[3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide(3.5 mg, 11%)

ESI-MS [M+H⁺]=429 Calculated for C₂₂H₂₅FN₄O₂S=428

Example 210cis-N-((2-Amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide

The compound was prepared in the same manner as the compound of example203 starting from the compound of example 208.

ESI-MS [M+H⁺]=455 Calculated for C₂₄H₂₇FN₄O₂S=454

Biological Testing

1. [³H]-Glycine uptake into recombinant CHO cells expressing humanGlyT1: Human GlyT1c expressing recombinant hGlyT1c_(—)5_CHO cells wereplated at 20,000 cells per well in 96 well Cytostar-T scintillationmicroplates (Amersham Biosciences) and cultured to sub-confluency for 24h. For glycine uptake assays the culture medium was aspirated and thecells were washed once with 100 μl HBSS (Gibco BRL, #14025-050) with 5mM L-Alanine (Merck #1007). 80 μl HBSS buffer were added, followed by 10μl inhibitor or vehicle (10% DMSO) and 10 μl [³H]-glycine (TRK71,Amersham Biosciences) to a final concentration of 200 nM for initiationof glycine uptake. The plates were placed in a Wallac Microbeta(PerkinElmer) and continuously counted by solid phase scintillationspectrometry during up to 3 hours. Nonspecific uptake was determined inthe presence of 10 μM Org24598. IC₅₀ calculations were made byfour-parametric logistic nonlinear regression analysis (GraphPad Prism)using determinations within the range of linear increase of [³H]-glycineincorporation between 60 and 120 min.

2. Radioligand binding assays using recombinant CHO cell membranesexpressing human GlyT1:

Radioligand binding to human GlyT1c transporter-expressing membranes wasdetermined as described in Mezler et al., Molecular Pharmacology74:1705-1715, 2008.

The following results were obtained with the compounds disclosed in theexamples:

TABLE 1 radioligand binding Example K_(iapp) [μM] 195 ≦1 196 ≦10 197≦0.1 198 ≦10 199 ≦0.01 200 ≦0.1 201 ≦0.1 202 ≦0.01 203 ≦0.1 204 ≦0.1 205≦0.1 206 ≦0.1 207 ≦1 209a ≦0.01 209b ≦0.01 210 ≦0.01

We claim:
 1. A method for treating a neurologic or psychiatric disorderor pain in a mammalian patient in need thereof, wherein the neurologicdisorder is selected from the group consisting of dementia, cognitiveimpairment, and attention deficit disorder, and the psychiatric disorderis selected from the group consisting of anxiety disorder, depression,bipolar disorder, schizophrenia, and psychosis; the method comprisingadministering to the patient a therapeutically effective amount of acompound of formula (I)

wherein A is a 5- or 6-membered ring; R is R¹—W-A¹-Q-Y-A²-X¹—; R¹ ishydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenatedC₁-C₆-alkyl, tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl, C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, halogenated C₁-C₆-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl,(halogenated C₁-C₄-alkyl)aminocarbonyl, C₆-C₁₂-arylaminocarbonyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl,hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, amino-C₁-C₄-alkoxy,C₁-C₆-alkylamino-C₁-C₄-alkoxy, di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino,di-(halogenated C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,(halogenated C₁-C₆-alkyl)carbonylamino, C₆-C₁₂-arylcarbonylamino,C₁-C₆-alkylsulfonylamino, (halogenated C₁-C₆-alkyl)sulfonylamino,C₆-C₁₂-arylsulfonylamino or optionally substituted C₃-C₁₂-heterocyclyl;W is —NR⁸— or a bond; A¹ is optionally substituted C₁-C₄-alkylene or abond; Q is —S(O)₂— or —C(O)—; Y is —NR⁹— or a bond; A² is optionallysubstituted C₁-C₄-alkylene, C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene,C₁-C₄-alkylene-O—C₁-C₄-alkylene, C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene,optionally substituted C₂-C₄-alkenylen, optionally substitutedC₂-C₄-alkynylene, optionally substituted C₆-C₁₂-arylene, optionallysubstituted C₆-C₁₂-heteroarylene or a bond; X¹ is —O—, —NR¹¹—, —S—,optionally substituted C₁-C₄-alkylene, optionally substitutedC₂-C₄-alkenylen, or optionally substituted C₂-C₄-alkynylene; R² ishydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionallysubstituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms ofA to which they are bound form a 5- or 6 membered ring.; R³ is hydrogen,halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or two radicals R³ together withthe carbon atom to which they are attached form a carbonyl group; R^(4a)is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, C₆-C₁₂-aryl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl,—CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl; R^(4b) is hydrogen, C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆, alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenatedC₁-C₄-alkyl)carbonyl, C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl,—C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-arylsulfonyl, C₆-C₁₂-arylsulfonyl, amino,—NO or C₃-C₁₂-heterocyclyl; or R^(4a) R^(4b) together are optionallysubstituted C₁-C₆-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may bereplaced by an oxygen atom or —NR¹⁶; X² is —O—, —NR⁶—, —S—,>CR^(12a)R^(12b) or a bond; X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or abond; R⁵ is optionally substituted C₆-C₁₂-aryl, optionally substitutedC₃-C₁₂-cycloalkyl or optionally substituted C₃-C₁₂-heterocyclyl; R⁶ ishydrogen or C₁-C₆-alkyl; R⁷ is hydrogen or C₁-C₆-alkyl; R⁸ is hydrogenor C₁-C₆-alkyl; R⁹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl,amino-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl-C₁-C₄-alkyl orC₃-C₁₂-heterocyclyl; or R⁹, R¹ together are C₁-C₄-alkylene; or R⁹ isC₁-C₄-alkylene that is bound to a carbon atom in A² and A² isC₁-C₄-alkylene or to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene; R¹⁰is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl; R¹¹ is hydrogen orC₁-C₆-alkyl, or R⁹, R¹¹ together are C₁-C₄-alkylene, R^(12a) ishydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(12b) is hydrogen or C₁-C₆-alkyl, or R^(12a), R^(12b)together are carbonyl or optionally substituted C₁-C₄-alkylene, whereinone —CH₂—of C₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁴—;R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(13b) is hydrogen or C₁-C₆-alkyl, or R^(13a), R^(13b)together are carbonyl or optionally substituted C₁-C₄-alkylene, whereinone —CH₂ of C₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁵—;R¹⁴ is hydrogen or C₁-C₆-alkyl; R¹⁵ is hydrogen or C₁-C₆-alkyl; and R¹⁶is hydrogen or C₁-C₆-alkyl, or a physiologically tolerated salt thereof.2. The method of claim 1, wherein A is a benzene ring.
 3. The method ofclaim 1, wherein —Y-A²-X¹— comprises at least 2, 3 or 4 atoms in themain chain.
 4. The method of claim 1, wherein R¹ is C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl, or optionallysubstituted C₃-C₁₂-heterocyclyl.
 5. The method of claim 1, wherein A¹ isa bond.
 6. The method of claim 1, wherein W is a bond and Y is a bond,or W is a bond and Y is —NR⁹—.
 7. The method of claim 1, wherein X¹ is—O— and A² is C₁-C₄-alkylene, or X¹ is C₁-C₄-alkylene and A² is a bond.8. The method of claim 1, wherein R¹—W-A¹-Q-Y-A²-X¹— isR¹—S(O)₂—NR⁹-A²-X¹— or R¹—S(O)₂—X¹—.
 9. The method of claim 1, whereinthe compound of formula (I) has the formula


10. The method of claim 1, wherein R^(4a) is C₁-C₆ alkyl,C₃-C₁₂-cycloalkyl, C₁-C₄-alkoxycarbonyl or C₃-C₁₂-heterocyclyl.
 11. Themethod of claim 1, wherein R^(4b) is hydrogen.
 12. The method of claim1, wherein R^(4a), R^(4b) together are optionally substitutedC₁-C₆-alkylene, wherein one —CH₂— of C₁-C₆-alkylene may be replaced byan oxygen atom.
 13. The method of claim 1, wherein X² isCR^(12a)R^(12b), and X³ is a bond.
 14. The method of claim 1, whereinR^(12a) is hydrogen or C₁-C₆-alkyl and R^(12b) is hydrogen orC₁-C₆-alkyl, or R^(12a), R^(12b) together are optionally substitutedC₁-C₄-alkylene.
 15. The method of claim 1, wherein R⁵ is optionallysubstituted aryl.
 16. The method of claim 1, wherein the compound offormula (I) has the formula


17. The method of claim 1, wherein A is a benzene ring; R isR¹—W-A¹-Q-Y-A²-X¹—; R¹ is C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl, or optionally substituted C₃-C₁₂-heterocyclyl; W is abond; A¹ is a bond; Q is —S(O)₂—; Y is —NR⁹— or a bond; A² isC₁-C₄-alkylene or a bond; X¹ is —O— or C₁-C₄-alkylene; R² is hydrogen orhalogen; R³ is hydrogen; R^(4a) is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl, C₁-C₄-alkoxycarbonyl or C₃-C₁₂-heterocyclyl; R^(4b)is hydrogen; or R^(4a), R^(4b) together are optionally substitutedC₁-C₆-alkylene, wherein one —CH₂— of C₁-C₄-alkylene may be replaced byan oxygen atom; X² is CR^(12a)R^(12b); X³ is a bond; R⁵ is optionallysubstituted phenyl; R⁹ is hydrogen; or R⁹ is C₁-C₄-alkylene that isbound to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene; R^(12a) ishydrogen; and R^(12b) is hydrogen; or R^(12a), R^(12b) together areC₁-C₄-alkylene.
 18. The method of claim 1, wherein the compound offormula (I) is:N-(2-((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;1-benzyl-6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;1-benzyl-6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-11-methyl-1H-imidazole-4-sulfonamide;1-benzyl-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-((3-benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-benzyl-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-(2-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;1-benzyl-6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;1-benzyl-6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;1-benzyl-5-fluoro-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-((3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-benzyl-5-fluoro-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)methyl)-cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)-azetidine;N-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;N-(2-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;1-cyclopropyl-N-(24(3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5yl)oxy)ethyl)methanesulfonamide;N-(2-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-cyclopropyl-N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)methanesulfonamide;1-(3-fluorobenzyl)-6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-1-(3-fluorobenzyl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;1-(3-fluorobenzyl)-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-((3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-(3-fluorobenzyl)-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;1-cyclopropyl-N-(2-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)methanesulfonamide;N-(2-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-cyclopropyl-N-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)methanesulfonamide;6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-1-(3-fluorobenzyl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-1-(3-fluorobenzyl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;5-fluoro-1-(3-fluorobenzyl)-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-((6-fluoro-3-(3-fluorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;5-fluoro-1-(3-fluorobenzyl)-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-(3-fluorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-fluorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;N-(2-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;1-(3-chlorobenzyl)-6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;1-(3-chlorobenzyl)-6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;1-(3-chlorobenzyl)-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-((3-(3-chlorobenzyl)-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-(3-chlorobenzyl)-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;1-(3-chlorobenzyl)-6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;1-(3-chlorobenzyl)-6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-2,3-dihydro-1H-inden-2-amine;N-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;1-(3-chlorobenzyl)-5-fluoro-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-((3-(3-chlorobenzyl)-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-(3-chlorobenzyl)-5-fluoro-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-2,3-dihydro-1H-inden-2-amine;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-chlorobenzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;1-cyclopropyl-N-(2-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)methanesulfonamide;N-(2-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;1-methyl-N-(2-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1H-imidazole-4-sulfonamide;1-methyl-N-(2-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1H-pyrazole-4-sulfonamide;1-cyclopropyl-N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)methanesulfonamide;6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;1-methyl-N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5yl)methyl)-1H-imidazole-4-sulfonamide;N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;1-methyl-N-((2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1H-pyrazole-4-sulfonamide;N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;1-cyclopropyl-N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)methanesulfonamide;N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;1-cyclopropyl-N-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)methanesulfonamide;6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;6-(1-((cyclopropylmethyl)sulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;6-(1-(cyclobutylsulfonyl)azetidin-3-yl)-5-fluoro-N-methyl-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;N-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;5-fluoro-N-methyl-6-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;N-((6-fluoro-2-(methylamino)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;5-fluoro-N-methyl-6-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)azetidin-3-yl)-1-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-2-amine;N-(2-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;N-(2-((2-(azetidin-1-yl)-3-(3-trifluoromethyl)benzyl)-6-fluoro-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-cyclopropylmethanesulfonamide;N-(2-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)cyclobutanesulfonamide;N-(2-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-cyclopropylmethanesulfonamide;3-(2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)-1-((cyclopropylmethyl)sulfonyl)azetidine;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)cyclobutanesulfonamide;3-(2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)-1-(cyclobutylsulfonyl)azetidine;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-imidazole;N-((2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-pyrazole-4-sulfonamide;4-((3-(2-(azetidin-1-yl)-6-fluoro-3-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-5yl)azetidin-1-yl)sulfonyl)-1-methyl-1H-pyrazole;N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;cis-N-(2-(2-Amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;Ethyl 1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate; Ethyl1-benzyl-6-(2-(1-methyl-1H-imidazole-2-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate;N-{2-[(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yl)oxy]ethyl}-1-methyl-1H-imidazole-4-sulfonamide;N-(2-(2-Amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-2-sulfonamide;N-(2-(3-Benzyl-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;cis-N-(2-(3-Benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;cis-N-(2-{[2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-(2-(Azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-(3-Benzyl-6-fluoro-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-(3-Benzyl-2-(3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-{[3-Benzyl-2-(3,3-dimethylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide;cis-N-(2-{[3-benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide;N-(2-(3-Benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-N,1-dimethyl-1H-imidazole-4-sulfonamide;Ethyl1-Benzyl-5-fluoro-6-((1-methyl-1H-imidazole-4-sulfonamido)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate;cis-N-{[3-Benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide;trans-N-{[3-Benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yl]methyl}-1-methyl-1H-imidazole-4-sulfonamide;orcis-N-((2-Amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide;or a physiologically tolerated salt thereof.
 19. A method for inhibitingthe glycine transporter GlyT1 in a mammal in need thereof whichcomprises the administration of an effective amount of a compound offormula (I)

wherein A is a 5- or 6-membered ring; R is R¹—W-A¹-Q-Y-A²-X¹—; R¹ ishydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenatedC₁-C₆-alkyl, tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄ alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl, C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, halogenated C₁-C₆-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl,(halogenated C₁-C₄-alkyl)aminocarbonyl, C₆-C₁₂-arylaminocarbonyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl,hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, amino-C₁-C₄-alkoxy,C₁-C₆-alkylamino-C₁-C₄-alkoxy, di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₆-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino,di-(halogenated C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,(halogenated C₁-C₆-alkyl)carbonylamino, C₆-C₁₂-arylcarbonylamino,C₁-C₆-alkylsulfonylamino, (halogenated C₁-C₆-alkyl)sulfonylamino,C₆-C₁₂-arylsulfonylamino or optionally substituted C₃-C₁₂-heterocyclyl;W is —NR⁸— or a bond; A¹ is optionally substituted C₁-C₄-alkylene or abond; Q is —S(O)₂— or —C(O)—; Y is —NR⁹— or a bond; A² is optionallysubstituted C₁-C₄-alkylene, C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene,C₁-C₄-alkylene-O—C₁-C₄-alkylene, C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene,optionally substituted C₂-C₄-alkenylen, optionally substitutedC₂-C₄-alkynylene, optionally substituted C₆-C₁₂-arylene, optionallysubstituted C₆-C₁₂-heteroarylene or a bond; X¹ is —O—, —NR¹¹—, —S—,optionally substituted C₁-C₄-alkylene, optionally substitutedC₂-C₄-alkenylen, or optionally substituted C₂-C₄-alkynylene; R² ishydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionallysubstituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms ofA to which they are bound form a 5- or 6 membered ring; R³ is hydrogen,halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or two radicals R³ together withthe carbon atom to which they are attached form a carbonyl group; R^(4a)is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, C₆-C₁₂-aryl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl,—CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl; R^(4b) is hydrogen, C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, —CHO, C₁-C₄-alkylcarbonyl, (halogenatedC₁-C₄-alkyl)carbonyl, C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl,—C(═NH)NH₂, —C(═NH)NHCN, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl,amino, —NO or C₃-C₁₂-heterocyclyl; or R^(4a)R^(4b) together areoptionally substituted C₁-C₆-alkylene, wherein one —CH₂— ofC₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁶; X² is —O—,—NR⁶—, —S—, >CR^(12a)R^(12b) or a bond; X³ is —O—, —NR⁷—, —S—,>CR^(13a)R^(13b) or a bond; R⁵ is optionally substituted C₆-C₁₂-aryl,optionally substituted C₃-C₁₂-cycloalkyl or optionally substitutedC₃-C₁₂-heterocyclyl; R⁶ is hydrogen or C₁-C₆-alkyl; R⁷ is hydrogen orC₁-C₆-alkyl; R⁸ is hydrogen or C₁-C₆-alkyl; R⁹ is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl, amino-C₁-C₆-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl or C₃-C₁₂-heterocyclyl; or R⁹, R¹ together areC₁-C₄-alkylene; or R⁹ is C₁-C₄-alkylene that is bound to a carbon atomin A² and A² is C₁-C₄-alkylene or to a carbon atom in X¹ and X¹ isC₁-C₄-alkylene; R¹ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl; R¹¹is hydrogen or C₁-C₆-alkyl, or R⁹, R¹¹ together are C₁-C₄-alkylene,R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(12b) is hydrogen or C₁-C₆-alkyl, or R^(12a), R^(12b)together are carbonyl or optionally substituted C₁-C₄-alkylene, whereinone —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁴—;R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(13b) is hydrogen or C₁-C₆-alkyl, or R^(13a), R^(13b)together are carbonyl or optionally substituted C₁-C₄-alkylene, whereinone —CH₂— of C₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁵—;R¹⁴ is hydrogen or C₁-C₆-alkyl; R¹⁵ is hydrogen or C₁-C₆-alkyl; and R¹⁶is hydrogen or C₁-C₆-alkyl, or a physiologically tolerated salt thereof.